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All five families of luminescent beetle, Phengodidae, Rhagophthalidae, Elateridae, Sinopyrophoridae, and Lampyridae are categorized into the Lampyroid clade. It has been determined that the luciferases and luciferin protein expressed in the photocytes of all species of firefly is homologous with that expressed in beetle species within the families Phengodidae, Rhagophthalidae, and Elateridae. In fact, every bioluminescent beetle species studied has been shown to use very similar mechanisms for light production in the photocyte. The beetle genus, Sinopyrophoridae, has been shown to exhibit biolumiescence although the exact mechanism is not known. It is believed that it shares homology with other genera of beetles however. The first time the entire genome of a bioluminescent beetle was determined was in 2017 with Pyrocoelia pectoralis, a species of firefly, and in 2018, three more species of bioluminescent beetle had their genomes sequenced. Biolumiescence in beetles has been shown to serve multiple purposes including the deterrence of predators and the attraction of mates. The variation in coloring among different species of firefly has been determined to be due to differences in the amino acid sequences of the luciferases expressed in their photocytes. Two luciferace genes have been identified in the genomes of fireflies. They are luc1-type and luc2-type. There is evidence that suggests that Luc1-type evolved from a gene duplication of the gene that encodes for acyl-CoA synthetase. It is hypothesized that the luciferase of click beetles evolved separately from that in fireflies being the result of two gene duplications of the acyl-CoA synthetase gene suggesting analogy instead of homology between the groups. Additional genes have been found to be related to the storage of luciferin.

Bioluminescence

* BMS-986121: μ-PAM * BMS-986122: μ-PAM * Ignavine * Oxytocin: μ-PAM * δ-PAM (see reference) * Cannabidiol * Tetrahydrocannabinol * Sodium (Na)

Neurochemistry

Sertraline and amitriptyline inhibit butyrylcholinesterase and cause prolonged paralysis. Mivacurium causes prolonged paralysis for patients chronically taking sertraline.

Neurochemistry

During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron. Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades. Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium. Expression appears to be exclusive, so that both types of endocannabinoids are not co-synthesized. This exclusion is based on synthesis-specific channel activation: a recent study found that in the bed nucleus of the stria terminalis, calcium entry through voltage-sensitive calcium channels produced an L-type current resulting in 2-AG production, while activation of mGluR1/5 receptors triggered the synthesis of anandamide. Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme called transacylase. This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine (NAPE). Experiments have shown that phospholipase D cleaves NAPE to yield anandamide. This process is mediated by bile acids. In NAPE-phospholipase D (NAPEPLD)-knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished, suggesting multiple, distinct pathways are involved in anandamide synthesis. The synthesis of 2-AG is less established and warrants further research. Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase (MAGL), and 2-AG into arachidonic acid and glycerol. While arachidonic acid is a substrate for leukotriene and prostaglandin synthesis, it is unclear whether this degradative byproduct has unique functions in the central nervous system. Emerging data in the field also points to FAAH being expressed in postsynaptic neurons complementary to presynaptic neurons expressing cannabinoid receptors, supporting the conclusion that it is major contributor to the clearance and inactivation of anandamide and 2-AG after endocannabinoid reuptake. A neuropharmacological study demonstrated that an inhibitor of FAAH (URB597) selectively increases anandamide levels in the brain of rodents and primates. Such approaches could lead to the development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompanied by overt signs of abuse liability.

Neurochemistry

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na, K, Ca, and/or Cl to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter. When a presynaptic neuron is excited, it releases a neurotransmitter from vesicles into the synaptic cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron. If these receptors are ligand-gated ion channels, a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization, for an excitatory receptor response, or a hyperpolarization, for an inhibitory response. These receptor proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allosteric binding site). This modularity has enabled a divide and conquer approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.

Neurochemistry

The chemical reaction that is responsible for bio-luminescence is catalyzed by the enzyme luciferase. In the presence of oxygen, luciferase catalyzes the oxidation of an organic molecule called luciferin. Though bio-luminescence across a diverse range of organisms such as bacteria, insects, and dinoflagellates function in this general manner (utilizing luciferase and luciferin), there are different types of luciferin-luciferase systems. For bacterial bio-luminescence specifically, the biochemical reaction involves the oxidation of an aliphatic aldehyde by a reduced flavin mononucleotide. The products of this oxidation reaction include an oxidized flavin mononucleotide, a fatty acid chain, and energy in the form of a blue-green visible light. Reaction: FMNH + O + RCHO → FMN + RCOOH + HO + light

Bioluminescence

Among the TrkA agonists, the small molecule gambogic amide exerts a potent neurotrophic activity decreasing apoptosis in primary hippocampal neurons. The non-peptidic TrkA agonist MT2 protects neurons from Aβ amyloid-mediated death in NGF-deficient neurons and talaumidin and its derivatives show neuroprotective effects, promoting neurite outgrowth in PC12 cells. Furthermore, the peptidomimetic cerebrolysin is known for its protective role in Alzheimer’s disease (AD). It was shown to improve the activities of daily living and the psychiatric symptoms in patients with mild to severe form of AD, after intravenous administration in a double-blind trial. In addition, the cyclic peptide tavilermide (MIM-D3), acting as a partial TrkA receptor agonist, showed a relevant improvement of cognitive capacities of treated aged rats, leading to a selective survival of the cholinergic neurons. A phase 3 clinical trial of 5% and 1% tavilermide ophthalmic solutions for the treatment of dry eye was completed in 2020 (NCT03925727), with positive results concerning safety and efficacy. Recent studies demonstrated the neurotrophic activity of carvacrol by inducing neurite outgrowth and phosphorylation of TrkA in cells deprived of NGF. The same research group investigated the neurotrophic effect of the well-known antibiotic doxycycline and they found that it prevents amyloid toxicity in a Drosophila model of AD both in vitro and in vivo and induces neuritogenesis by activation of TrkA. Additionally, some novel DHEA derivatives were shown to be TrkA agonists. In particular, the C17-spiroepoxy derivative, BNN-27, induces phosphorylation of TrkA in neuronal and glial cells in culture and it exerts antiapoptotic effect without inducing hyperalgesia. Moreover, it improved memorizing abilities in rats after i.p. administration and restored the myelin loss in cuprizone-induced demyelination in vivo. Moreover, the C17-spirocyclopryl DHEA derivatives, ENT-A010 and ENT-A013, were shown to be potent TrkA agonists. In particular, ENT-A010 acts as dual TrkA and TrkB agonist while, ENT-A013 acts as a selective TrkA agonist. Both induce phosphorylation of TrkA and its downstream signaling pathways, and promote cell survival of PC12 cells from serum deprivation. In addition, they exhibit potent neuroprotective effects in dorsal root ganglia and anti-amyloid activity in hippocampal neurons.

Neurochemistry

A number of different structural domains that fold mostly on their own have been found in the APP sequence. The extracellular region, much larger than the intracellular region, is divided into the E1 and E2 domains, linked by an acidic domain (AcD); E1 contains two subdomains including a growth factor-like domain (GFLD) and a copper-binding domain (CuBD) interacting tightly together. A serine protease inhibitor domain, absent from the isoform differentially expressed in the brain, is found between acidic region and E2 domain. The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the growth factor-like domain, the copper-binding domain, the complete E1 domain and the E2 domain.

Neurochemistry

Photoactivated guanylyl cyclases have been discovered in the aquatic fungi Blastocladiella emersonii and Catenaria anguillulae. Unlike PACs, these light-activated cyclases use retinal as their light sensor and are therefore rhodopsin guanylyl cyclases (RhGC). When expressed in Xenopus oocytes or mammalian neurons, RhGCs generate cGMP in response to green light. Therefore, they are considered useful optogenetic tools to investigate cGMP signaling.

Neurochemistry

Clinical neurochemistry is the field of neurological biochemistry which relates biochemical phenomena to clinical symptomatic manifestations in humans. While neurochemistry is mostly associated with the effects of neurotransmitters and similarly functioning chemicals on neurons themselves, clinical neurochemistry relates these phenomena to system-wide symptoms. Clinical neurochemistry is related to neurogenesis, neuromodulation, neuroplasticity, neuroendocrinology, and neuroimmunology in the context of associating neurological findings at both lower and higher level organismal functions.

Neurochemistry

These drugs fall into two groups: *Non-depolarizing blocking agents: These agents constitute the majority of the clinically relevant neuromuscular blockers. They act by competitively blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors. *Depolarizing blocking agents: These agents act by depolarizing the sarcolemma of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh.

Neurochemistry

Adrenaline stimulates photocytes to emit light for many species of fish. It is believed that sympathetic nervous impulses provide the stimulus that causes photocytes to emit light.

Bioluminescence

The endocannabinoid system is by molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicative of biosynthetic plasticity and potential physiological roles of endocannabinoid-like lipids in plants, and detection of arachidonic acid (AA) indicates chemotaxonomic connections between monophyletic groups with common ancestor dates to around 500 million years ago (Cambrian). The phylogenetic distribution of these lipids may be a consequence of interactions/adaptations to the surrounding conditions such as chemical plant-pollinator interactions, communication and defense mechanisms. The two novel EC-like molecules derived from the eicosatetraenoic acid juniperonic acid, an omega-3 structural isomer of AA, namely juniperoyl ethanolamide and 2-juniperoyl glycerol (1/2-AG) in gymnosperms, lycophytes and few monilophytes, show AA is an evolutionarily conserved signalling molecule that acts in plants in response to stress similar to that in animal systems. The endocannabinoid Docosatetraenoylethanolamide has been found in Tropaeolum tuberosum (Mashua) and Leonotis leonurus (Lion's tail) Maca contains several N-benzylamides referred to as "macamides" that are structurally related to endocannabinoids such as the N-Benzyl analog of Oleamide. Echinacea contains alkylamides structurally related to endocannabinoids.

Neurochemistry

Homovanillic acid (HVA) is a major catecholamine metabolite that is produced by a consecutive action of monoamine oxidase and catechol-O-methyltransferase on dopamine. Homovanillic acid is used as a reagent to detect oxidative enzymes, and is associated with dopamine levels in the brain. In psychiatry and neuroscience, brain and cerebrospinal fluid levels of HVA are measured as a marker of metabolic stress caused by 2-deoxy--glucose. HVA presence supports a diagnosis of neuroblastoma and malignant pheochromocytoma. Fasting plasma levels of HVA are known to be higher in females than in males. This does not seem to be influenced by adult hormonal changes, as the pattern is retained in the elderly and post-menopausal as well as transgender people according to their genetic sex, both before and during cross-sex hormone administration. Differences in HVA have also been correlated to tobacco usage, with smokers showing significantly lower amounts of plasma HVA.

Neurochemistry

The light-producing chemistry behind bioluminescence varies across the lineages of bioluminescent organisms. Based on this observation, bioluminescence is believed to have evolved independently at least 40 times. In bioluminescent bacteria, the reclassification of the members ofVibrio fischeri species group as a new genus, Aliivibrio, has led to increased interest in the evolutionary origins of bioluminescence. Among bacteria, the distribution of bioluminescent species is polyphyletic. For instance, while all species in the terrestrial genus Photorhabdus are luminescent, the genera Aliivibrio, Photobacterium, Shewanella and Vibrio contain both luminous and non-luminous species. Despite bioluminescence in bacteria not sharing a common origin, they all share a gene sequence in common. The appearance of the highly conserved lux operon in bacteria from very different ecological niches suggests a strong selective advantage despite the high energetic costs of producing light. DNA repair is thought to be the initial selective advantage for light production in bacteria. Consequently, the lux operon may have been lost in bacteria that evolved more efficient DNA repair systems but retained in those where visible light became a selective advantage. The evolution of quorum sensing is believed to have afforded further selective advantage for light production. Quorum sensing allows bacteria to conserve energy by ensuring that they do not synthesize light-producing chemicals unless a sufficient concentration are present to be visible.

Bioluminescence

SK3 (small conductance calcium-activated potassium channel 3) also known as K2.3 is a protein that in humans is encoded by the KCNN3 gene. SK3 is a small-conductance calcium-activated potassium channel partly responsible for the calcium-dependent after hyperpolarisation current (I). It belongs to a family of channels known as small-conductance potassium channels, which consists of three members – SK1, SK2 and SK3 (encoded by the KCNN1, 2 and 3 genes respectively), which share a 60-70% sequence identity. These channels have acquired a number of alternative names, however a NC-IUPHAR has recently achieved consensus on the best names, K2.1 (SK1), K2.2 (SK2) and K2.3 (SK3). Small conductance channels are responsible for the medium and possibly the slow components of the I.

Neurochemistry

Roderick MacKinnon commissioned Birth of an Idea, a tall sculpture based on the KcsA potassium channel. The artwork contains a wire object representing the channel's interior with a blown glass object representing the main cavity of the channel structure.

Neurochemistry

A repeat polymorphism of cytosines and adenines (CA) was found to be near BCYRN1 and was used as a reference for mapping the gene. Linkage mapping and radiation hybrid mapping localized the BCYRN1 gene to chromosome 2p16. As a long non-coding cytoplasmic RNA, BC200 RNA is a part of the largest group of non-coding transcripts in the human genome, which is more prevalent than protein coding genes. The 5' region (left arm) of monomeric Alu short interspersed repetitive elements (SINEs) allows for BC200 RNA transposition and has been evolutionarily conserved in other primates. Of this group of SINEs, BC200 is one of few that are transcriptionally active. In humans, it is found in neuropil areas which are composed of predominantly unmyelinated dendrites, axons, and glial cells. Similarly, the functional analog of BC200 RNA in rodents (BC1 RNA) is expressed largely in somatodendritic domains of the nervous system, making it an ideal model for experimentation. One large difference is in origin; BC200 emerged from retrotransposed Alu domain, while BC1 originated from retrotransposed tRNA. Although they evolved separately, both are not usually expressed in non-neural somatic cells, with the exception of tumors.

Neurochemistry

An amino acid neurotransmitter is an amino acid which is able to transmit a nerve message across a synapse. Neurotransmitters (chemicals) are packaged into vesicles that cluster beneath the axon terminal membrane on the presynaptic side of a synapse in a process called endocytosis. Amino acid neurotransmitter release (exocytosis) is dependent upon calcium Ca and is a presynaptic response.

Neurochemistry

Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonists, excitatory amino acid receptor antagonists, and excitatory amino acid reuptake inhibitors.

Neurochemistry

Because channels underlie the nerve impulse and because "transmitter-activated" channels mediate conduction across the synapses, channels are especially prominent components of the nervous system. Indeed, numerous toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g., the venoms produced by spiders, scorpions, snakes, fish, bees, sea snails, and others) work by modulating ion channel conductance and/or kinetics. In addition, ion channels are key components in a wide variety of biological processes that involve rapid changes in cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation, and pancreatic beta-cell insulin release. In the search for new drugs, ion channels are a frequent target.

Neurochemistry

The SK channel family contains 4 members – SK1, SK2, SK3, and SK4. SK4 is often referred to as IK (Intermediate conductance) due to its higher conductance 20 – 80 pS.

Neurochemistry

p75NTR functions in a complex with Nogo-66 receptor (NgR1) to mediate RhoA-dependent inhibition of growth of regenerating axons exposed to inhibitory proteins of CNS myelin, such as Nogo, MAG or OMgP. Without p75NTR, OMgP can activate RhoA and inhibit CNS axon regeneration. Coexpression of p75NTR and OMgP suppress RhoA activation. A complex of NgR1, p75NTR and LINGO1 can activate RhoA.

Neurochemistry

There are two classes of receptors for neurotrophins: p75 and the "Trk" family of Tyrosine kinases receptors.

Neurochemistry

The wide-ranged biological purposes of bio-luminescence include but are not limited to attraction of mates, defense against predators, and warning signals. In the case of bioluminescent bacteria, bio-luminescence mainly serves as a form of dispersal. It has been hypothesized that enteric bacteria (bacteria that survive in the guts of other organisms) - especially those prevalent in the depths of the ocean - employ bio-luminescence as an effective form of distribution. After making their way into the digestive tracts of fish and other marine organisms and being excreted in fecal pellets, bioluminescent bacteria are able to utilize their bio-luminescent capabilities to lure in other organisms and prompt ingestion of these bacterial-containing fecal pellets. The bio-luminescence of bacteria thereby ensures their survival, persistence, and dispersal as they are able to enter and inhabit other organisms.

Bioluminescence

Excitatory amino acids (EAA) will activate post-synaptic cells. inhibitory amino acids (IAA) depress the activity of post-synaptic cells.

Neurochemistry

Alzheimers disease (AD) is the most common cause of dementia in the elderly. AD is a neurodegenerative disease characterized by the loss of cognitive functioning - thinking, remembering and reasoning- and behavioral abilities to such an extent that it interferes with a persons daily life and activities. The neuropathological hallmarks of AD include amyloid plaques and neurofibrillary tangles, which lead to neuronal death. Studies in animal models of AD have shown that p75NTR contributes to amyloid β-induced neuronal damage. In humans with AD, increases in p75NTR expression relative to TrkA have been suggested to be responsible for the loss of cholinergic neurons. Increases in proNGF in AD indicate that the Neurotrophin environment is favorable for p75NTR/sortilin signaling and supports the theory that age-related neural damage is facilitated by a shift toward proNGF-mediated signaling. A recent study found that activation of Ngfr signaling in astroglia of Alzheimers disease mouse model enhanced neurogenesis and reduced two hallmarks of Alzheimers disease. This study also found that NGFR signaling in humans is age-related and correlates with proliferative potential of neural progenitors.

Neurochemistry

The need for fluorescently tracking RNA rose as its roles in complex cellular functions has grown to not only include mRNA, rRNA, and tRNA, but also RNAi, siRNA, snoRNA, and lncRNA, among others. Spinach is a synthetically derived RNA aptamer born out of the need for a way of studying the role of RNAs at the cellular level. This aptamer was created using Systematic Evolution for Ligands by EXponential enrichment, or SELEX, which is also known as in vitro evolution. The aptamer was designed to be an RNA mimic of green fluorescent protein (GFP); similar to GFP for proteins, Spinach can be used for the fluorescently labeling RNA and tracking it in vivo. A method for inserting the Spinach sequence after an RNA sequence of interest is readily available. GFP’s fluorophore is made up of three cyclized amino acids within the beta-barrel structure: Serine65-Tyrosine66-Glycine67. This structure, 4-hydroxybenzylidene imidazolinone (HBI) was the basis for the synthetic analogue used in the SELEX studies. Many derivatives of this structure were screened using SELEX, but the chosen fluorophore, 3,5-difluoro-4-hydroxybenzylidene imidazolinone (DFHBI), showed the best selective fluorescence with high quantum yield (0.72) when bound to the RNA sequence 24-2, deemed Spinach. It was determined that DFHBI only binds Spinach in the phenolate form. At pH < 6.0, both the phenolic and phenolate forms are detected. At pH = 6.0, only the phenolate peak is detected. DFHBI is also incredibly robust and resists photobleaching over a long period of time as compared to HBI and EGFP. It is believed that the free exchange of bound and unbound ligand allows for this persistence. As the fluorophore of GFP and its derivatives are covalently bound to/a part of the protein, free exchange cannot happen and thus photobleaching results. Spinach is an 84-nucleotide-long structure with two helical strands and an internal bulge with a G-quadruplex motif. It is at this G-quadruplex that the fluorophore binds. Based on crystallographic data, massive rearrangement of the adjacent bases occurs once the fluorophore binds to accommodate the molecule. This binding is favorable, however, as it promotes base-stacking in a normally unstable region, i.e. the internal bulge. Similar to GFP, the DFHBI is also dehydrated, which would help with its high quantum yield. Spinach has also been adapted for sensing proteins or molecules in vivo. An adapted structure, which includes two binding sites, limits fluorescence of the aptamer to (1) the fluorophore and (2) the protein or small molecule.

Bioluminescence

Photoactivated adenylyl cyclase (PAC) is a protein consisting of an adenylyl cyclase enzyme domain directly linked to a BLUF (blue light receptor using FAD) type light sensor domain. When illuminated with blue light, the enzyme domain becomes active and converts ATP to cAMP, an important second messenger in many cells. In the unicellular flagellate Euglena gracilis, PACα and PACβ (euPACs) serve as a photoreceptor complex that senses light for photophobic responses and phototaxis. Small but potent PACs were identified in the genome of the bacteria Beggiatoa (bPAC) and Oscillatoria acuminata (OaPAC). While natural bPAC has some enzymatic activity in the absence of light, variants with no dark activity have been engineered (PACmn).

Neurochemistry

The Gill Mantle ("Txampaysye" in Navi) is a large jellyfish like creature native to Pandoras reefs. The Navi can bond with them in the water, which can supply them with oxygen through the water allowing Navi to remain underwater much longer. They are primarily used by Kiri throughout Avatar: The Way of Water.

Bioluminescence

The word proteomics was first used in 1994 by Marc Wilkins as the study of “the protein equivalent of a genome”. It is defined as all of the proteins expressed in a biological system under specific physiologic conditions at a certain point in time. It can change with any biochemical alteration, and so it can only be defined under certain conditions. Neuroproteomics is a subset of this field dealing with the complexities and multi-system origin of neurological disease. Neurological function is based on the interactions of many proteins of different origin, and so requires a systematic study of subsystems within its proteomic structure.

Neurochemistry

In some clinical circumstances, succinylcholine may be administered before and after a nondepolarising NMBA or two different nondepolarising NMBAs are administered in sequence. Combining different NMBAs can result in different degrees of neuromuscular block and management should be guided with the use of a neuromuscular function monitor. The administration of nondepolarising neuromuscular blocking agent has an antagonistic effect on the subsequent depolarising block induced by succinylcholine. If a nondepolarising NMBA is administered prior to succinycholine, the dose of succinylcholine must be increased. The administration of succinylcholine on the subsequent administration of a nondepolarising neuromuscular block depends on the drug used. Studies have shown that administration of succinylcholien before a nondepolarising NMBA does not affect the potency of mivacurium or rocuronium. But for vecuronium and cisatracurium, it speeds up the onset, increases the potency and prolongs the duration of action. Combining two nondepolarising NMBAs of the same chemical class (e.g. rocuronium and vecuronium) produces an additive effect, while combining two nondepolarising NMBAs of different chemical class (e.g. rocuronium and cisatracurium) produces a synergistic response.

Neurochemistry

FET framework was proposed to simplify classifications of psychiatric disorders (DSM, ICD) using 12 functional aspects of behaviour that this model highlights. Clinical studies showed good differential power of the FET framework for various diagnoses of psychopathology. For example, depressed people had low endurance and psychomotor slowdown in their temperament profiles. In contrast to them, patients with Generalized Anxiety Disorder had higher impulsivity and neuroticism. FET-developers suggested that every symptom in DSM/ICD diagnoses can be mapped into a specific FET code reflecting a disregulation within well-documented neurochemical systems.

Neurochemistry

Aequorin is presumably encoded in the genome of Aequorea. At least four copies of the gene were recovered as cDNA from the animal. Because the genome has not been sequenced, it is unclear if the cDNA variants can account for all of the isoforms of the protein.

Bioluminescence

The thanator (Palulukan in Navi) is a large hexapodal land predator that is believed, by the RDA, to be the apex land predator. It is scientifically known as Bestiapanthera ferox. Cameron personally designed the creature. The thanator is first seen when Jake wanders off into the jungle and touches multiple helicoradian leaves, at which they retract to reveal a family of hammerhead titanotheres behind. The thanator frightens the titanotheres and pursues Jake. Jake later escapes the thanator by jumping off a cliff into pool below. It later appears during the climax where it assists Neytiri and later battles Quaritchs AMP Suit Beyond Glory, but is killed by the AMP suit's knife. The thanator is black with white fleshy skin under each hand. Its appearance is similar to a panther; Cameron describes the thanator as "the panther from hell". The thanator has ten sensory quills connected to six pads at the rear of the skull that flare up before it attacks the prey. The director explained how the thanator is the most fearsome creature on Pandora, "The thanator could eat a T-Rex and have the Alien for dessert."

Bioluminescence

In dendritic spines, SK channels are directly coupled to NMDA receptors. In addition to being activated by calcium flow through voltage-gated calcium channels, SK channels can be activated by calcium flowing through NMDA receptors, which occurs after depolarization of the postsynaptic membrane. Experiments using apamin have shown that specifically blocking SK channels can increase learning and long-term potentiation. In addition, brain-derived neurotrophic factor (BDNF) causes the down-regulation of SK channels, which facilitates long-term potentiation. Increasing SK channel activity has the opposite effect and serves to impair learning. An increase in SK channel activity that occurs over time may be related to decreases in plasticity and memory that is seen with aging.

Neurochemistry

Mechanical stimulation to spines on the arm can cause Amphiura filiformis to bioluminesce in the blue range. The species has been found to possess a luciferase compound. The luciferase has been isolated to clusters of photocytes that exist at the tip off the arms and around the spines. What are believed to be photocytes based on evidence have been found around the spine nerve plexus, mucus cells, and what are believed to be pigment cells. It has been found that luminescence is controlled by the animal's nervous system. Acetylcholine is able to stimulate the cells through nicotinic receptors.

Bioluminescence

In the 1960s and 1970s, GFP, along with the separate luminescent protein aequorin (an enzyme that catalyzes the breakdown of luciferin, releasing light), was first purified from the jellyfish Aequorea victoria and its properties studied by Osamu Shimomura. In A. victoria, GFP fluorescence occurs when aequorin interacts with Ca ions, inducing a blue glow. Some of this luminescent energy is transferred to the GFP, shifting the overall color towards green. However, its utility as a tool for molecular biologists did not begin to be realized until 1992 when Douglas Prasher reported the cloning and nucleotide sequence of wtGFP in Gene. The funding for this project had run out, so Prasher sent cDNA samples to several labs. The lab of Martin Chalfie expressed the coding sequence of wtGFP, with the first few amino acids deleted, in heterologous cells of E. coli and C. elegans, publishing the results in Science in 1994. Frederick Tsuji's lab independently reported the expression of the recombinant protein one month later. Remarkably, the GFP molecule folded and was fluorescent at room temperature, without the need for exogenous cofactors specific to the jellyfish. Although this near-wtGFP was fluorescent, it had several drawbacks, including dual peaked excitation spectra, pH sensitivity, chloride sensitivity, poor fluorescence quantum yield, poor photostability and poor folding at . The first reported crystal structure of a GFP was that of the S65T mutant by the Remington group in Science in 1996. One month later, the Phillips group independently reported the wild-type GFP structure in Nature Biotechnology. These crystal structures provided vital background on chromophore formation and neighboring residue interactions. Researchers have modified these residues by directed and random mutagenesis to produce the wide variety of GFP derivatives in use today. Further research into GFP has shown that it is resistant to detergents, proteases, guanidinium chloride (GdmCl) treatments, and drastic temperature changes.

Bioluminescence

Protein separate techniques, such as 2D PAGE, are limited in that they cannot handle very high or low molecular weight protein species. Alternative methods have been developed to deal with such cases. These include liquid chromatography mass spectrometry along with sodium dodecyl sulfate polyacrylamide gel electrophoresis, or liquid chromatography mass spectrometry run in multiple dimensions. Compared to simple 2D page, liquid chromatography mass spectrometry can handle a larger range of protein species size, but it is limited in the amount of protein sample it handle at once. Liquid chromatography mass spectrometry is also limited in its lack of a reference map from which to work with. Complex algorithms are usually used to analyze the fringe results that occur after a procedure is run. The unknown portions of the protein species are usually not analyzed in favor of familiar proteomes, however. This fact reveals a fault with current technology; new techniques are needed to increase both the specificity and scope of proteome mapping.

Neurochemistry

The Pandoran biosphere is a fictional habitat introduced in James Camerons 2009 science fiction film Avatar. The ecology of the lush exomoon Pandora, which teems with a biodiversity of bioluminescent species ranging from hexapodal animals to other types of exotic fauna and flora, forms a vast neural network spanning the entire lunar surface into which the Navi and other creatures can connect. The strength of this collective consciousness is illustrated when the human invaders are defeated in battle by the Pandoran ecology, after the Na'vi are nearly defeated. Cameron utilized a team of expert advisors to make the various examples of fauna and flora as scientifically feasible as possible.

Bioluminescence

The regulation of bio-luminescence in bacteria is achieved through the regulation of the oxidative enzyme called luciferase. It is important that bio-luminescent bacteria decrease production rates of luciferase when the population is sparse in number in order to conserve energy. Thus, bacterial bioluminescence is regulated by means of chemical communication referred to as quorum sensing. Essentially, certain signaling molecules named autoinducers with specific bacterial receptors become activated when the population density of bacteria is high enough. The activation of these receptors leads to a coordinated induction of luciferase production that ultimately yields visible luminescence.

Bioluminescence

Neuropeptidergic means "related to neuropeptides". A neuropeptidergic agent (or drug) is a chemical which functions to directly modulate the neuropeptide systems in the body or brain. An example is opioidergics.

Neurochemistry

Very few parts of the sympathetic system use cholinergic receptors. In sweat glands the receptors are of the muscarinic type. The sympathetic nervous system also has some preganglionic nerves terminating at the chromaffin cells in the adrenal medulla, which secrete epinephrine and norepinephrine into the bloodstream. Some believe that chromaffin cells are modified postganglionic CNS fibers. In the adrenal medulla, acetylcholine is used as a neurotransmitter, and the receptor is of the nicotinic type. The somatic nervous system uses a nicotinic receptor to acetylcholine at the neuromuscular junction.

Neurochemistry

A photophore is a glandular organ that appears as luminous spots on various marine animals, including fish and cephalopods. The organ can be simple, or as complex as the human eye; equipped with lenses, shutters, color filters and reflectors, however unlike an eye it is optimized to produce light, not absorb it. The bioluminescence can variously be produced from compounds during the digestion of prey, from specialized mitochondrial cells in the organism called photocytes ("light producing" cells), or, similarly, associated with symbiotic bacteria in the organism that are cultured. The character of photophores is important in the identification of deep sea fishes. Photophores on fish are used for attracting food or for camouflage from predators by counter-illumination. Photophores are found on some cephalopods including the firefly squid, which can create impressive light displays, as well as numerous other deep sea organisms such as the pocket shark Mollisquama mississippiensis and the strawberry squid.

Bioluminescence

Neurotrophin binding to p75NTR activates the c-Jun N-terminal kinases (JNK) signaling pathway causing apoptosis of developing neurons. JNK, through a series of intermediates, activates p53 and p53 activates Bax which initiates apoptosis. TrkA can prevent p75NTR-mediated JNK pathway apoptosis.

Neurochemistry

Excitotoxicity can occur from substances produced within the body (endogenous excitotoxins). Glutamate is a prime example of an excitotoxin in the brain, and it is also the major excitatory neurotransmitter in the central nervous system of mammals. During normal conditions, glutamate concentration can be increased up to 1mM in the synaptic cleft, which is rapidly decreased in the lapse of milliseconds. When the glutamate concentration around the synaptic cleft cannot be decreased or reaches higher levels, the neuron kills itself by a process called apoptosis. This pathologic phenomenon can also occur after brain injury and spinal cord injury. Within minutes after spinal cord injury, damaged neural cells within the lesion site spill glutamate into the extracellular space where glutamate can stimulate presynaptic glutamate receptors to enhance the release of additional glutamate. Brain trauma or stroke can cause ischemia, in which blood flow is reduced to inadequate levels. Ischemia is followed by accumulation of glutamate and aspartate in the extracellular fluid, causing cell death, which is aggravated by lack of oxygen and glucose. The biochemical cascade resulting from ischemia and involving excitotoxicity is called the ischemic cascade. Because of the events resulting from ischemia and glutamate receptor activation, a deep chemical coma may be induced in patients with brain injury to reduce the metabolic rate of the brain (its need for oxygen and glucose) and save energy to be used to remove glutamate actively. (The main aim in induced comas is to reduce the intracranial pressure, not brain metabolism). Increased extracellular glutamate levels leads to the activation of Ca permeable NMDA receptors on myelin sheaths and oligodendrocytes, leaving oligodendrocytes susceptible to Ca influxes and subsequent excitotoxicity. One of the damaging results of excess calcium in the cytosol is initiating apoptosis through cleaved caspase processing. Another damaging result of excess calcium in the cytosol is the opening of the mitochondrial permeability transition pore, a pore in the membranes of mitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release reactive oxygen species and other proteins that can lead to apoptosis. The pore can also cause mitochondria to release more calcium. In addition, production of adenosine triphosphate (ATP) may be stopped, and ATP synthase may in fact begin hydrolysing ATP instead of producing it, which is suggested to be involved in depression. Inadequate ATP production resulting from brain trauma can eliminate electrochemical gradients of certain ions. Glutamate transporters require the maintenance of these ion gradients to remove glutamate from the extracellular space. The loss of ion gradients results in not only the halting of glutamate uptake, but also in the reversal of the transporters. The Na-glutamate transporters on neurons and astrocytes can reverse their glutamate transport and start secreting glutamate at a concentration capable of inducing excitotoxicity. This results in a buildup of glutamate and further damaging activation of glutamate receptors. On the molecular level, calcium influx is not the only factor responsible for apoptosis induced by excitoxicity. Recently, it has been noted that extrasynaptic NMDA receptor activation, triggered by both glutamate exposure or hypoxic/ischemic conditions, activate a CREB (cAMP response element binding) protein shut-off, which in turn caused loss of mitochondrial membrane potential and apoptosis. On the other hand, activation of synaptic NMDA receptors activated only the CREB pathway, which activates BDNF (brain-derived neurotrophic factor), not activating apoptosis.

Neurochemistry

Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include: altering intrinsic firing activity, increasing or decreasing voltage-dependent currents, altering synaptic efficacy, increasing bursting activity and reconfigurating synaptic connectivity. Major neuromodulators in the central nervous system include: dopamine, serotonin, acetylcholine, histamine, norepinephrine, nitric oxide, and several neuropeptides. Cannabinoids can also be powerful CNS neuromodulators. Neuromodulators can be packaged into vesicles and released by neurons, secreted as hormones and delivered through the circulatory system. A neuromodulator can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite. Some neuromodulators end up spending a significant amount of time in the cerebrospinal fluid (CSF), influencing (or "modulating") the activity of several other neurons in the brain.

Neurochemistry

Using Kickstarter, the project's founders raised $484,000 on June 8, 2013. This was significantly more than the initial target of $65,000. Seeds were initially scheduled to be delivered in April 2014, and subsequently scheduled for the fall of 2014. In March 2016, delivery of seeds was forecast for 2016 on the Glowing Plant website. The company encountered difficulty in producing plants that emit significant amounts of light, resulting in a transition to producing moss that emits a patchouli scent. They later announced via email December 2017 that the company was permanently ceasing operations.

Bioluminescence

Photochemical conversion occurs due to interactions between the chromophoric unit and residues in its vicinity. Glu-212 functions as a base that removes a proton from His-62 aiding in the cleavage of the His-62-Nα-Cα bond. Replacing Glu-212 with glutamine prevents photoconversion. At low pH, the yield of Eos involved in photoconversion is greatly increased as the fraction of molecules in the protonated form increases. The action spectrum for photoconversion is closely related to the action spectrum for Eos's protonated form. These observations suggest that the neutral form of the green chromophore, including a protonated Tyr-63 side chain, is the gateway structure for photoconversion. Proton ejection from the Tyr-63 phenyl side chain is an important event in the conversion mechanism where a proton is transferred from the His-62 imidazole, which is hydrogen-bonded to the Phe-61 carbonyl. The extra proton causes His-62 to donate a proton to the Phe-61 carbonyl forming a leaving group out of the peptide bond between His and Phe in the elimination reaction. The His-62 side chain is protonated during photoexcitation and assists the reaction by donating a proton to the Phe-61 carbonyl in the leaving group. After the backbone is cleaved, the hydrogen bond between His-62 and Phe-61 is reformed. When His-62 is replaced with other amino acids, EosFP loses its ability to photoconvert, providing evidence that His-62 is a necessary component of the photoconversion mechanism. The internal charge distribution of the green chromophore is altered during photo excitation to assist in the elimination reaction.

Bioluminescence

Photoactivatable fluorescent proteins (PAFPs) is a type of fluorescent protein that exhibit fluorescence that can be modified by a light-induced chemical reaction.

Bioluminescence

Gallamine triethiodide is originally developed for preventing muscle contractions during surgical procedures. However, it is no longer marketed in the United States according to the FDA orange book.

Neurochemistry

The M muscarinic receptors are located in the heart and lungs. In the heart, they act to slow the heart rate down below the normal baseline sinus rhythm, by slowing the speed of depolarization. In humans, under resting conditions, vagal activity dominates over sympathetic activity. Hence, inhibition of M receptors (e.g. by atropine) will cause a raise in heart rate. They also moderately reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). It also serves to slightly decrease the contractile forces of the ventricular muscle. M muscarinic receptors act via a G type receptor, which causes a decrease in cAMP in the cell, inhibition of voltage-gated Ca channels, and increasing efflux of K, in general, leading to inhibitory-type effects.

Neurochemistry

Neurotransmitter systems are systems of neurons in the brain expressing certain types of neurotransmitters, and thus form distinct systems. Activation of the system causes effects in large volumes of the brain, called volume transmission. Volume transmission is the diffusion of neurotransmitters through the brain extracellular fluid released at points that may be remote from the target cells with the resulting activation of extrasynaptic receptors, and with a longer time course than for transmission at a single synapse. Such prolonged transmitter action is called tonic transmission, in contrast to the phasic transmission that occurs rapidly at single synapses.

Neurochemistry

Scintillons are small structures in cytoplasm that produce light. Among bioluminescent organisms, only dinoflagellates have scintillons.

Bioluminescence

JNK can directly phosphorylate Bim-EL, a splicing isoform of Bcl-2 interacting mediator of cell death (Bim), which activates Bim-EL apoptotic activity. JNK activation is required for apoptosis but c-jun, a protein in the JNK signaling pathway, is not always required.

Neurochemistry

Induced metabolic bioluminescence imaging (imBI) is used to obtain a metabolic snapshot of biological tissues. Metabolites that may be quantified through imBI include glucose, lactate, pyruvate, ATP, glucose-6-phosphate, or D2-hydroxygluturate. imBI can be used to determine the lactate concentration of tumors or to measure the metabolism of the brain.

Bioluminescence

K2.3 channels play a major role in human physiology, particularly in smooth muscle relaxation. The expression level of K2.3 channels in the endothelium influences arterial tone by setting arterial smooth muscle membrane potential. The sustained activity of K2.3 channels induces a sustained hyperpolarisation of the endothelial cell membrane potential, which is then carried to nearby smooth muscle through gap junctions. Blocking the K2.3 channel or suppressing K2.3 expression causes a greatly increased tone in resistance arteries, producing an increase in peripheral resistance and blood pressure.

Neurochemistry

At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem. As many of these fibers are primarily GABAergic, cannabinoid stimulation in the spinal column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuli-processing in the periphery and dorsal root ganglion. The endocannabinoid most researched in pain is palmitoylethanolamide. Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor, the TRPV receptor and the GPR55 receptor. Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications and found to be safe and effective. Modulation of the endocannabinoid system by metabolism to N-arachidinoyl-phenolamine (AM404), an endogenous cannabinoid neurotransmitter, has been discovered to be one mechanism for analgesia by acetaminophen (paracetamol). Endocannabinoids are involved in placebo induced analgesia responses.

Neurochemistry

Low-affinity nerve growth factor receptor has been shown to interact with: * FSCN1, * MAGEH1, * NDN, * NGFRAP1 * NGF, * PRKACB, * TRAF2, and * TRAF4. *Nogo-66 receptor *c-Jun N-terminal kinases * RhoA * Rho GDP dissociation inhibitor (RhoGDI) *NF-kB *Neurotrophin-3 *Brain-derived neurotrophic factor *Neurotrophin-4

Neurochemistry

Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB receptor is expressed presynaptically by motor neurons that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves. Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.

Neurochemistry

Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB and CB receptors, which are expressed predominantly in the brain and immune system respectively. Density of expression varies based on species and correlates with the efficacy that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum, regions of the brain involved in the initiation and coordination of movement. In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps explain why cannabinoids possess a greater efficacy in altering rodent motor movements than they do in humans. A recent analysis of cannabinoid binding in CB and CB receptor knockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain. Binding has been demonstrated by 2-arachidonoylglycerol (2-AG) on the TRPV1 receptor suggesting that this receptor may be a candidate for the established response. In addition to CB1 and CB2, certain orphan receptors are known to bind endocannabinoids as well, including GPR18, GPR55 (a regulator of neuroimmune function), and GPR119. CB1 has also been noted to form a functional human receptor heterodimer in orexin neurons with OX1, the CB1–OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced pressor responses which are known to occur through signaling in the rostral ventrolateral medulla.

Neurochemistry

By the time Loewi began his experiments there was much discussion among scientists whether communication between nerves and muscles was chemical or electrical by nature. Experiments by Luigi Galvani in the 18th century had demonstrated that electrical stimulation of the frog sciatic nerve resulted in twitching of the leg muscles, and from this he developed the concept of bioelectricity. This led to the idea that direct electrical contact between nerves and muscles mediated transmission of excitation. However, work by John Newport Langley had suggested that in the autonomic nervous system communication in the ciliary ganglion was chemical. Loewi's experiments, published in 1921, finally settled the issue, proving that synaptic transmission was chemical. Loewi performed a very simple yet elegant experiment. Using an isolated frog heart he had previously found that stimulation of the vagus nerve resulted in a slowing of the heart rate, while stimulation of the sympathetic nerve caused the heart rate to speed up (Figure 1). He reasoned that stimulation of either the vagus or sympathetic nerve would cause the nerve terminal to release a substance which would either slow or accelerate the heart rate. To prove this, he took a frog heart, which had been cannulated in order to perfuse the fluid surrounding the heart, and electrically stimulated the vagus nerve until the heart rate slowed. He then collected the fluid surrounding the heart and added it to a second frog heart which had been stripped of its vagal and sympathetic nerves. By adding the fluid surrounding the first heart to the second heart, he caused the heart rate of the second heart to slow down. This proved that stimulation of the vagus nerve caused the release of a substance which acted upon the heart tissue and directly caused the heart rate to slow down. (Figure 2) This substance was called vagusstoff. Vagustoff was later confirmed to be acetylcholine and was found to be the principal neurotransmitter in the parasympathetic nervous system. In an interesting aside, Loewi apparently had the idea for his experiment in a dream. He wrote it down in the middle of the night but the next morning could not decipher his writing. He eventually had the same dream on another night, and decided to run to the laboratory to perform the experiment in the middle of the night. About this incident, Loewi writes: :On mature consideration, in the cold light of the morning, I would not have done it. After all, it was an unlikely enough assumption that the vagus should secrete an inhibitory substance; it was still more unlikely that a chemical substance that was supposed to be effective at very close range between nerve terminal and muscle be secreted in such large amounts that it would spill over and, after being diluted by the perfusion fluid, still be able to inhibit another heart. (Loewi 1921) Loewi was fortunate in his choice of experimental preparation. In the species of frog used (Rana esculenta), the vagus contains both inhibitory and stimulatory fibers. In the winter, inhibitory fibers predominate, so Loewi was also fortunate to have performed his experiments in February or March. Additionally, acetylcholinesterase activity (the enzyme that degrades acetylcholine) is low, particularly in an unheated laboratory, allowing the neurotransmitter to remain long enough to be collected and applied to a second heart. Thanks to this confluence of events, Loewi was able to describe the existence of vagusstoff and prove the existence of chemical synaptic transmission.

Neurochemistry

Also at the Janelia Research Campus, a new fluorescent molecules known as CaMPARI (calcium-modulated photoactivatable ratiometric integrator) was developed using EosFP. The permanent green to red conversion signal was coupled with a calcium-sensitive protein, calmodulin, so that color change in the fusion construct depended on the release of calcium accompanied by neural activity. CaMPARI is able to permanently mark neurons that are active at an any time and can also be targeted to synapses. This visualization is possible across a wide amount of brain tissue as opposed to the limited view available with using a microscope. It also allows for the visualization of neural activity during complicated behaviors as the organism under study is allowed to move freely, rather than under a microscope. It also allows for the observation of neurons during specific behavior periods. CaMPARI has, thus far, been used to label active neural circuits in mice, zebrafish and fruit flies.

Bioluminescence

Bioluminescence is the process of light emission in living organisms. Bioluminescence imaging utilizes native light emission from one of several organisms which bioluminesce, also known as luciferase enzymes. The three main sources are the North American firefly, the sea pansy (and related marine organisms), and bacteria like Photorhabdus luminescens and Vibrio fischeri. The DNA encoding the luminescent protein is incorporated into the laboratory animal either via a viral vector or by creating a transgenic animal. Rodent models of cancer spread can be studied through bioluminescence imaging.for e.g.Mouse models of breast cancer metastasis. Systems derived from the three groups above differ in key ways: * Firefly luciferase requires D-luciferin to be injected into the subject prior to imaging. The peak emission wavelength is about 560 nm. Due to the attenuation of blue-green light in tissues, the red-shift (compared to the other systems) of this emission makes detection of firefly luciferase much more sensitive in vivo. * Renilla luciferase (from the Sea pansy) requires its substrate, coelenterazine, to be injected as well. As opposed to luciferin, coelenterazine has a lower bioavailability (likely due to MDR1 transporting it out of mammalian cells). Additionally, the peak emission wavelength is about 480 nm. * Bacterial luciferase has an advantage in that the lux operon used to express it also encodes the enzymes required for substrate biosynthesis. Although originally believed to be functional only in prokaryotic organisms, where it is widely used for developing bioluminescent pathogens, it has been genetically engineered to work in mammalian expression systems as well. This luciferase reaction has a peak wavelength of about 490 nm. While the total amount of light emitted from bioluminescence is typically small and not detected by the human eye, an ultra-sensitive CCD camera can image bioluminescence from an external vantage point.

Bioluminescence

Luciferases can be produced in the lab through genetic engineering for a number of purposes. Luciferase genes can be synthesized and inserted into organisms or transfected into cells. As of 2002, mice, silkworms, and potatoes are just a few of the organisms that have already been engineered to produce the protein. In the luciferase reaction, light is emitted when luciferase acts on the appropriate luciferin substrate. Photon emission can be detected by light sensitive apparatus such as a luminometer or an optical microscope with a CCD camera. This allows observation of biological processes. Since light excitation is not needed for luciferase bioluminescence, there is minimal autofluorescence and therefore the bioluminescent signal is virtually background-free. Therefore, as little as 0.02 pg can still be accurately measured using a standard scintillation counter. In biological research, luciferase is commonly used as a reporter to assess the transcriptional activity in cells that are transfected with a genetic construct containing the luciferase gene under the control of a promoter of interest. Additionally, proluminescent molecules that are converted to luciferin upon activity of a particular enzyme can be used to detect enzyme activity in coupled or two-step luciferase assays. Such substrates have been used to detect caspase activity and cytochrome P450 activity, among others. Luciferase can also be used to detect the level of cellular ATP in cell viability assays or for kinase activity assays. Luciferase can act as an ATP sensor protein through biotinylation. Biotinylation will immobilize luciferase on the cell-surface by binding to a streptavidin-biotin complex. This allows luciferase to detect the efflux of ATP from the cell and will effectively display the real-time release of ATP through bioluminescence. Luciferase can additionally be made more sensitive for ATP detection by increasing the luminescence intensity by changing certain amino acid residues in the sequence of the protein. Whole organism imaging (referred to as in vivo when intact or, otherwise called ex vivo imaging for example of living but explanted tissue) is a powerful technique for studying cell populations in live plants or animals, such as mice. Different types of cells (e.g. bone marrow stem cells, T-cells) can be engineered to express a luciferase allowing their non-invasive visualization inside a live animal using a sensitive charge-couple device camera (CCD camera).This technique has been used to follow tumorigenesis and response of tumors to treatment in animal models. However, environmental factors and therapeutic interferences may cause some discrepancies between tumor burden and bioluminescence intensity in relation to changes in proliferative activity. The intensity of the signal measured by in vivo imaging may depend on various factors, such as -luciferin absorption through the peritoneum, blood flow, cell membrane permeability, availability of co-factors, intracellular pH and transparency of overlying tissue, in addition to the amount of luciferase. Luciferase is a heat-sensitive protein that is used in studies on protein denaturation, testing the protective capacities of heat shock proteins. The opportunities for using luciferase continue to expand.

Bioluminescence

Neuromelanin (NM) is a dark pigment found in the brain which is structurally related to melanin. It is a polymer of 5,6-dihydroxyindole monomers. Neuromelanin is found in large quantities in catecholaminergic cells of the substantia nigra pars compacta and locus coeruleus, giving a dark color to the structures.

Neurochemistry

Alzheimers disease is the most common cause of severe memory impairment and is caused by senile plaques, neurofibrillary tangles, dystrophic neuritis, and neuronal loss. It is thought that Alzheimers disease may be due to unnecessary protein accumulation of β Amyloid. In fact, Senile plaques are dense, protein deposits composed of amyloid β peptide. The two types of senile plaques are diffuse plaques and neuritic plaques, and differ in morphology. In addition to the amyloid, the microtubule-associated Tau protein has also been in involved with Alzheimers disease and a variety of other neurodegenerative diseases. Inherited forms of Alzheimers have been linked to mutation in the APP genes or presenilins which regulate APP processing. Because cholinergic neurons of the nucleus basalis are significantly altered during Alzheimer's progression, cholinergic agents such as choline and lecithin were hypothesized to augment the progression. However, these attempts were unsuccessful and the only clinically useful drugs used in the United States are cholinesterase inhibitors, which prolong the time before choline degradation. Although receptor antagonists and anti-inflammatory drugs were tested in a clinical environment, more promising clinical trials are underway to targeting the Aβ with the immune system.

Neurochemistry

The amyloid-β precursor protein (AβPP), and all associated secretases, are expressed early in development and play a key role in the endocrinology of reproduction – with the differential processing of AβPP by secretases regulating human embryonic stem cell (hESC) proliferation as well as their differentiation into neural precursor cells (NPC). The pregnancy hormone human chorionic gonadotropin (hCG) increases AβPP expression and hESC proliferation while progesterone directs AβPP processing towards the non-amyloidogenic pathway, which promotes hESC differentiation into NPC. AβPP and its cleavage products do not promote the proliferation and differentiation of post-mitotic neurons; rather, the overexpression of either wild-type or mutant AβPP in post-mitotic neurons induces apoptotic death following their re-entry into the cell cycle. It is postulated that the loss of sex steroids (including progesterone) but the elevation in luteinizing hormone, the adult equivalent of hCG, post-menopause and during andropause drives amyloid-β production and re-entry of post-mitotic neurons into the cell cycle.

Neurochemistry

Life That Glows (also known as David Attenborough’s Light on Earth) is a 2016 British nature documentary programme made for BBC Television, first shown in the UK on BBC Two on 9 May 2016. The programme is presented and narrated by Sir David Attenborough. Life That Glows depicts the biology and ecology of bioluminescent organisms, that is, organisms capable of creating light. The programme features fireflies, who use light as a means of sexual attraction, luminous fungi, luminous marine bacteria responsible for the Milky seas effect, the flashlight fish, the aposematism of the Sierra luminous millipede, earthworms, and the bioluminescent tides created by blooms of dinoflagellates in Tasmania, as well as dolphins swimming in the bloom in the Sea of Cortez, the defensive flashes of brittle stars and ostracods, sexual attraction in ostracods, prey attraction by luminous click beetles in Cerrado, Brazil and Arachnocampa gnats in New Zealand. The programme then introduces many luminous deep sea animals, including the vampire squid, the polychaete worm Tomopteris that generates yellow light, the jellyfish Atolla, the comb jelly Beroe, the viper fish, pyrosomes, a dragonfish, and the polychaete worm Flota. Next, the programme discusses specialised adaptations in the eyes of particular animals to see bioluminescence, such as the barreleye fish and the cock-eyed squid. Lastly, the programme features the mass spawning event of the firefly squid in Japan.

Bioluminescence

As PACs consist of a light sensor and an enzyme in a single protein, they can be expressed in other species and cell types to manipulate cAMP levels with light. When bPAC is expressed in mouse sperm, blue light illumination speeds up the swimming of transgenic sperm cells and aids fertilization. When expressed in neurons, illumination changes the branching pattern of growing axons. PAC has been used in mice to clarify the function of neurons in the hypothalamus, which use cAMP signaling to control mating behavior. Expression of PAC together with K-specific cyclic-nucleotide-gated ion channels (CNGs) has been used to hyperpolarize neurons at very low light levels, which prevents them from firing action potentials.

Neurochemistry

*Dystonia: involuntary muscle contractions *Axial hypotonia: low muscle tone and strength *Dysarthria: impairment in muscles used for speech *Muscle stiffness and tremors *Seizures *Coordination and balance impairment *Oculogyric crises: abnormal rotation of the eyes The oculogyric crises usually occur in the later half of the day and during these episodes patients undergo extreme agitation and irritability along with uncontrolled head and neck movements. Apart from the aforementioned symptoms, patients can also display parkinsonism, sleep disturbances, small head size (microcephaly), behavioral abnormalities, weakness, drooling, and gastrointestinal symptoms.

Neurochemistry

Huntingtons disease is characterized by cognitive impairments. There is increased expression of p75NTR in the hippocampus of Huntingtons disease patients (including mice models and humans). Over expression of p75NTR in mice causes cognitive impairments similar to Huntingtons disease. p75NTR is linked to reduced numbers of dendritic spines in the hippocampus, likely through p75NTR interactions with Transforming protein RhoA. Modulating p75NTR function could be a future direction in treating Huntingtons disease.

Neurochemistry

Coelenterazine is widely found in marine organisms including: *radiolarians *ctenophores *cnidarians such as Aequorea victoria, Obelia geniculata and Renilla reniformis *squid such as Watasenia scintillans and Vampyroteuthis infernalis *shrimp such as Systellaspis debilis and Oplophorus gracilirostris *copepods such as Pleuromamma xiphias and Gaussia princeps *chaetognaths *fish including some Neoscopelidae and Myctophidae *echinoderms such as Amphiura filiformis The compound has also been isolated from organisms that are not luminescent, such as the Atlantic herring and several shrimp species including Pandalus borealis and Pandalus platyuros.

Bioluminescence

Neuroproteomics has the difficult task of defining on a molecular level the pathways of consciousness, senses, and self. Neurological disorders are unique in that they do not always exhibit outward symptoms. Defining the disorders becomes difficult and so neuroproteomics is a step in the right direction of identifying bio-markers that can be used to detect diseases. Not only does the field have to map out the different proteins possible from the genome, but there are many modifications that happen after transcription that affect function as well. Because neurons are such dynamic structures, changing with every action potential that travels through them, neuroproteomics offers the most potential for mapping out the molecular template of their function. Genomics offers a static roadmap of the cell, while proteomics can offer a glimpse into structures smaller than the cell because of its specific nature to each moment in time.

Neurochemistry

The austrapede (Tspìng in Navi) is a Pandoran creature that resembles a cross between an ostrich, a pink flamingo and the herbivorous dinosaur Parasaurolophus. The Austrapede has yellow-orange skin with faint purple striping, a long, flat beak, and a flat tail reaching down to its feet. Unlike other Pandoran birds and its relative, the great austrapede, the austrapedes wings have shrunken down to small, vestigial appendages, and much of its height is made up by its legs and neck. Austrapedes flap their wings when frightened. The austrapedes are impulsive, fidgety creatures whose emotions spread quickly from one individual to the other by a form of mimicry. Relatively small by Pandoran standards, Austrapedes generally pose little threat to other creatures, and are sometimes affectionate to Navi. They first appear in the musical, Toruk – The First Flight'.

Bioluminescence

A neurochemical is a small organic molecule or peptide that participates in neural activity. The science of neurochemistry studies the functions of neurochemicals.

Neurochemistry

Marine dinoflagellates at night can emit blue light by bioluminescence, a process also called "the phosphorescence of the seas". Light production in these single celled organisms is produced by small structures in the cytoplasm called scintillons. Among bioluminescent organisms, only dinoflagellates have scintillons. In the dinoflagellates, the biochemical reaction that produces light involves a luciferase-catalysed oxidation of a linear tetrapyrrole called luciferin. The dinoflagellate Lingulodinium polyedra (previously called Gonyaulax polyedra) also contains a second protein called luciferin binding protein (LBP) that has been proposed to protect luciferin from non-luminescent oxidation. Luciferin is released from LBP by a decrease in pH, and the same decreased pH also activates the luciferase. Light production in the dinoflagellates occurs in bioluminescent organelles called scintillons and can be stimulated by agitation of the surrounding seawater.

Bioluminescence

In neurons of the human brain, somatic recombination occurs frequently in the gene that encodes APP. Neurons from individuals with sporadic Alzheimers disease show greater APP' gene diversity due to somatic recombination than neurons from healthy individuals.

Neurochemistry

Endocannabinoid reuptake inhibitors (eCBRIs), also called cannabinoid reuptake inhibitors (CBRIs), are drugs which limit the reabsorption of endocannabinoid neurotransmitters by the releasing neuron.

Neurochemistry

Monoaminergic means "working on monoamine neurotransmitters", which include serotonin, dopamine, norepinephrine, epinephrine, and histamine. A monoaminergic, or monoaminergic drug, is a chemical, which functions to directly modulate the serotonin, dopamine, norepinephrine, epinephrine, and/or histamine neurotransmitter systems in the brain. Monoaminergics include catecholaminergics (which can be further divided into adrenergics and dopaminergics), serotonergics, and histaminergics. Examples of monoaminergic drugs include monoamine precursors, monoamine receptor modulators, monoamine reuptake inhibitors, monoamine releasing agents, and monoamine metabolism modulators such as monoamine oxidase inhibitors.

Neurochemistry

The diagnosis of SR deficiency is based on the analysis of the pterins and biogenic amines found in the cerebrospinal fluid (CSF) of the brain. The pterin compound functions as a cofactor in enzyme catalysis and biogenic amines which include adrenaline, dopamine, and serotonin have functions that vary from the control of homeostasis to the management of cognitive tasks. This analysis reveals decreased concentrations of homovanillic acid (HVA), 5-hydroxyindolacetic acid (HIAA), and elevated levels of 7,8-dihydrobiopterin, a compound produced in the synthesis of neurotransmitters. Sepiapterin is not detected by the regularly used methods applied in the investigation of biogenic monoamine metabolites in the cerebrospinal fluid. It must be determined by specialized methods that work by indicating a marked and abnormal increase of sepiapterin in cerebrospinal fluid. Confirmation of the diagnosis occurs by demonstrating high levels of CSF sepiapterin and a marked decrease of SR activity of the fibroblasts along with SPR gene molecular analysis.

Neurochemistry

Coelenteramide is the oxidized product, or oxyluciferin, of the bioluminescent reactions in many marine organisms that use coelenterazine. It was first isolated as a blue fluorescent protein from Aequorea victoria after the animals were stimulated to emit light. Under basic conditions, the compound will break down further into coelenteramine and 4-hydroxyphenylacetic acid. It is an aminopyrazine.

Bioluminescence

Sortilin is required for many apoptosis-promoting p75NTR reactions, functioning as a co-receptor for the binding of neurotrophins such as BDNF. pro-neurotrophins (such as proBDNF) bind especially well to p75NTR when sortilin is present.

Neurochemistry

Also well studied is the sea pansy, Renilla reniformis. In this organism, the luciferase (Renilla-luciferin 2-monooxygenase) is closely associated with a luciferin-binding protein as well as a green fluorescent protein (GFP). Calcium triggers release of the luciferin (coelenterazine) from the luciferin binding protein. The substrate is then available for oxidation by the luciferase, where it is degraded to coelenteramide with a resultant release of energy. In the absence of GFP, this energy would be released as a photon of blue light (peak emission wavelength 482 nm). However, due to the closely associated GFP, the energy released by the luciferase is instead coupled through resonance energy transfer to the fluorophore of the GFP, and is subsequently released as a photon of green light (peak emission wavelength 510 nm). The catalyzed reaction is: * coelenterazine + O → coelenteramide + CO + photon of light

Bioluminescence

Catecholaminergic cell groups refers to collections of neurons in the central nervous system that have been demonstrated by histochemical fluorescence to contain one of the neurotransmitters dopamine or norepinephrine. Thus, it represents the combination of dopaminergic cell groups and noradrenergic cell groups. Some authors include in this category putative adrenergic cell groups, collections of neurons that stain for PNMT, the enzyme that converts norepinephrine to epinephrine (adrenaline). Catecholaminergic cell groups and Parkinsons disease have an interactive relationship. Catecholaminergic neurons containing neuromelanin are more susceptible to Parkinsons related cell death than nonmelanized catecholaminergic neurons. Neuromelanin is an autoxidation byproduct of catecholamines, and it has been suggested that catecholaminergic neurons surrounded by a low density of glutathione peroxidase cells are more susceptible to degeneration in Parkinsons disease than those protected against oxidative stress. Hyperoxidation may be responsible for the selective degeneration of catecholaminergic neurons, specifically in the substantia nigra'.

Neurochemistry

Dark pigments in the substantia nigra were first described in 1838 by Purkyně, and the term neuromelanin was proposed in 1957 by Lillie, though it has been thought to serve no function until recently. It is now believed to play a vital role in preventing cell death in certain parts of the brain. It has been linked to Parkinson's disease and because of this possible connection, neuromelanin has been heavily researched in the last decade.

Neurochemistry

Biophotons (from the Greek βίος meaning "life" and φῶς meaning "light") are photons of light in the ultraviolet and low visible light range that are produced by a biological system. They are non-thermal in origin, and the emission of biophotons is technically a type of bioluminescence, though bioluminescence is generally reserved for higher luminance luciferin/luciferase systems. The term biophoton used in this narrow sense should not be confused with the broader field of biophotonics, which studies the general interaction of light with biological systems. Biological tissues typically produce an observed radiant emittance in the visible and ultraviolet frequencies ranging from 10 to 10 W/cm (approx 1-1000 photons/cm/second). This low level of light has a much weaker intensity than the visible light produced by bioluminescence, but biophotons are detectable above the background of thermal radiation that is emitted by tissues at their normal temperature. While detection of biophotons has been reported by several groups, hypotheses that such biophotons indicate the state of biological tissues and facilitate a form of cellular communication are still under investigation, Alexander Gurwitsch, who discovered the existence of biophotons, was awarded the Stalin Prize in 1941 for his work.

Bioluminescence

Another role for these receptors is at the junction of the innervated tissues and the postganglionic neurons in the parasympathetic division of the autonomic nervous system. Here acetylcholine is again used as a neurotransmitter, and muscarinic receptors form the principal receptors on the innervated tissue.

Neurochemistry

The main difference is in the reversal of these two types of neuromuscular-blocking drugs. * Non-depolarizing blockers are reversed by acetylcholinesterase inhibitor drugs since non-depolarizing blockers are competitive antagonists at the ACh receptor so can be reversed by increases in ACh. * The depolarizing blockers already have ACh-like actions, so these agents have prolonged effect under the influence of acetylcholinesterase inhibitors. Administration of depolarizing blockers initially produces fasciculations (a sudden twitch just before paralysis occurs). This is due to depolarization of the muscle. Also, post-operative pain is associated with depolarizing blockers. The tetanic fade is the failure of muscles to maintain a fused tetany at sufficiently high frequencies of electrical stimulation. * Non-depolarizing blockers have this effect on patients, probably by an effect on presynaptic receptors. * Depolarizing blockers do not cause the tetanic fade. However, a clinically similar manifestation called Phase II block occurs with repeated doses of suxamethonium. This discrepancy is diagnostically useful in case of intoxication of an unknown neuromuscular-blocking drug.

Neurochemistry

Cannabinoidergic, or cannabinergic, means "working on the endocannabinoid neurotransmitters". As with terms such as dopaminergic and serotonergic, related proteins and cellular components involved endocannabinoid signaling, such as the cannabinoid (CB) receptor, as well as exogenous compounds, such as phytocannabinoids or other cannabinoids which modulate the activity of endocannabinoid system, can be described as cannabinoidergic.

Neurochemistry

Bioluminescence has only been observed in three classes of mollusks: Cephalopoda, Gastropoda, and Bivalvia. Bioluminescence is widely spread among cephalopods, but much rarer among the other classes of mollusk. Most species of biolumenescent mollusk that have been discovered are found in the ocean with the exception of the genera Latia and Quantula found in freshwater and terrestrial habitats respectively; however, more recent research has discovered luminescence in the Phuphania genus. It is hypothesized that terrestrial mollusks that use bioluminescence developed it as a strategy to deter predation. The green color emanated by the mollusk's photocytes is thought to be the most visible color to nocturnal predators.

Bioluminescence

Chemical substances can modulate the activity of ion channels, for example by blocking or activating them.

Neurochemistry

Light production in Porichthys notatus has been found to be triggered through an adrenergic mechanism. The sympathetic nervous system of the fish is responsible for triggering bioluminescence in the photocytes. As a response to being triggered by an norepinepherine, epinephrine, or phenylephrine, the photocyte exhibits a quick flash and then emits light that slowly fades in intensity. Stimulation by isoproterenol was found to cause an only a slow fading illumination. The amplitude of the quick flash, referred to as the "fast response", was higher when the concentration of neurotransmitter stimulating it increased. A great dal of variation in luminescence was exhibited in the photocytes of different fish. Variation also existed depending on what time of year the photocytes were collected from the fish. Stimulation from phenylephrine was found to produce a less intense response than that of epinephrine or norepinephrine. Phentolamine was shown to inhibit the effect of stimulation by phenylephrine completely and of epinephrine and norepinephrine to a lesser degree. Clonidine was shown to have an inhibitory effect on the fast response but no effect on the slow response. The photocytes of Porichthys are known to be extensively innervated.

Bioluminescence

The protein structure of firefly luciferase consists of two compact domains: the N-terminal domain and the C-terminal domain. The N-terminal domain is composed of two β-sheets in an αβαβα structure and a β barrel. The two β-sheets stack on top of each other, with the β-barrel covering the end of the sheets. The C-terminal domain is connected to the N-terminal domain by a flexible hinge, which can separate the two domains. The amino acid sequences on the surface of the two domains facing each other are conserved in bacterial and firefly luciferase, thereby strongly suggesting that the active site is located in the cleft between the domains. During a reaction, luciferase has a conformational change and goes into a "closed" form with the two domains coming together to enclose the substrate. This ensures that water is excluded from the reaction and does not hydrolyze ATP or the electronically excited product.

Bioluminescence

The major neurotransmitter systems are the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system. Drugs targeting the neurotransmitter of such systems affect the whole system, which explains the mode of action of many drugs. Most other neurotransmitters, on the other hand, e.g. glutamate, GABA and glycine, are used very generally throughout the central nervous system.

Neurochemistry

Both the fluorescence excitation and emission spectrums of wild-type EosFP are shifted ~65 nm to the right upon excitation toward the red end of the spectrum. This spectral change is caused by an extension of the chromophore accompanied by a break in the peptide backbone between Phe-61 and His-62 in an irreversible mechanism. The presence of a crisp isosbestic point at 432 nm also suggests an interconversion between two species. An absorption peak at 280 nm is visible due to aromatic amino acids which transfer their excitation energy to the green chromophore. The quantum yield of the green-emitting form of Eos is 0.7. In the red shifted species, there are pronounced vibronic sidebands separate from the main peak at 533 nm and 629 nm in the excitation spectrum and emission spectrum respectively. There is another peak in the red excitation spectrum at 502 nm likely due to FRET excitation of the red fluorophore. The quantum yield of the red-emitting form is 0.55. EosFPs variants show almost no difference in spectroscopic properties, therefore, it is likely that the structural modifications which arise from separation of interfaces have little to no effect on the structure of the fluorophore-binding site.

Bioluminescence

Aequorin is a calcium-activated photoprotein isolated from the hydrozoan Aequorea victoria. Its bioluminescence was studied decades before the protein was isolated from the animal by Osamu Shimomura in 1962. In the animal, the protein occurs together with the green fluorescent protein to produce green light by resonant energy transfer, while aequorin by itself generates blue light. Discussions of "jellyfish DNA" that can make "glowing" animals often refer to transgenic animals that express the green fluorescent protein, not aequorin, although both originally derive from the same animal. Apoaequorin, the protein portion of aequorin, is an ingredient in the dietary supplement Prevagen. The US Federal Trade Commission (FTC) has charged the maker with false advertising for its memory improvement claims.

Bioluminescence

The AMPA receptor (AMPAR) is the engine that drives excitatory postsynaptic potentials (EPSPs). While some forms of the AMPAR can conduct calcium, most AMPARs found in the neocortex do not. The AMPAR, upon binding two glutamate molecules, undergoes a conformational change that resembles the opening of a clam shell. This conformational change opens an ion channel within the AMPAR protein structure that allows sodium ions to flow into the cell and potassium ions to flow out (i.e. it is a mixed cation-conducting channel). The Na and K permeabilities of the AMPAR channel are roughly equal, so when this channel is open the resulting change in membrane potential tends towards zero (a bit more than halfway between the equilibrium potentials E and E). This balance point is reached at around 0 mV (i.e. the reversal potential of the EPSP current is roughly 0 mV). However, the postsynaptic membrane potential will not change by more than a few millivolts from resting potential with a single presynaptic release of glutamate, because not many AMPAR channels open. The lifetime of the glutamate in the synaptic cleft is too short to allow more than a brief opening of the AMPAR channel, thus causing only a small depolarization. The open AMPAR channel is often considered to be non-calcium permeable, but this is only an approximation as AMPARs with certain subunit compositions will allow calcium through, albeit at different levels and frequency to NMDARs. Historically, the most widely used experimental means of inducing LTP has been to deliver a tetanic stimulation to the presynaptic axon of a synapse or group of synapses. The frequency of this tetanus is typically 100 Hz, and the duration typically 1 s. A single AMPAR-mediated EPSP has a rise time-to-peak of approximately 2–5 ms and a duration of approximately 30 ms. If a synapse is being stimulated at 100 Hz, the presynaptic neuron will be attempting to release glutamate once every 10 ms. An EPSP occurring only 10 ms after a previous EPSP will arrive at a time when that previous EPSP is at its peak amplitude. Thus, during a 100 Hz stimulus train, each EPSP will add to the membrane depolarization caused by the previous EPSPs. This synaptic summation drives the membrane potential toward values that could not be reached with single synaptic stimuli. As the EPSPs summate, they will exceed the spike threshold.

Neurochemistry

Curare is a crude extract from certain South American plants in the genera Strychnos and Chondrodendron, originally brought to Europe by explorers such as Walter Raleigh Edward Bancroft, a chemist and physician in the 16th century brought samples of crude curare from South America back to the Old-World. The effect of curare was experimented with by Sir Benjamin Brodie when he injected small animals with curare, and found that the animals stopped breathing but could be kept alive by inflating their lungs with bellows. This observation led to the conclusion that curare can paralyse the respiratory muscles. It was also experimented by Charles Waterton in 1814 when he injected three donkeys with curare. The first donkey was injected in the shoulder and died afterward. The second donkey had a tourniquet applied to the foreleg and was injected distal to the tourniquet. The donkey lived while the tourniquet was in place but died after it was removed. The third donkey after injected with curare appeared to be dead but was resuscitated using bellows. Charles Waterton's experiment confirmed the paralytic effect of curare. It was known in the 19th century to have a paralysing effect, due in part to the studies of scientists like Claude Bernard. D-tubocurarine a mono-quaternary alkaloid was isolated from Chondrodendron tomentosum in 1942, and it was shown to be the major constituent in curare responsible for producing the paralysing effect. At that time, it was known that curare and, therefore, d-tubocurarine worked at the neuromuscular junction. The isolation of tubocurarine and its marketing as the drug Intocostrin led to more research in the field of neuromuscular-blocking drugs. Scientists figured out that the potency of tubocurarine was related to the separation distance between the two quaternary ammonium heads. Neurologist Walter Freeman learned about curare and suggested to Richard Gill, a patient suffering from multiple sclerosis, that he try using it. Gill brought 25 pounds of raw curare from Ecuador. The raw curare was then given to Squibb and Sons to derive an effective antidote to curare. In 1942, Wintersteiner and Dutcher (two scientists working for Squibb and Sons) isolated the alkaloid d-tubocurarine. Soon after, they developed a preparation of curare called Intocostrin. At the same time in Montreal, Harold Randall Griffith and his resident Enid Johnson at the Homeopathic Hospital administered curare to a young patient undergoing appendectomy. This was the first use of NMBA as muscle relaxant in anesthesia. The 1940s, 1950s and 1960s saw the rapid development of several synthetic NMBA. Gallamine was the first synthetic NMBA used clinically. Further research led to the development of synthesized molecules with different curariform effects, depending on the distance between the quaternary ammonium groups. One of the synthesized bis-quaternaries was decamethonium a 10-carbon bis-quaternary compound. Following research with decamethonium, scientists developed suxamethonium, which is a double acetylcholine molecule that was connected at the acetyl end. The discovery and development of suxamethonium lead to a Nobel Prize in medicine in 1957. Suxamethonium showed different blocking effect in that its effect was achieved more quickly and augmented a response in the muscle before block. Also, tubocurarine effects were known to be reversible by acetylcholinesterase inhibitors, whereas decamethonium and suxamethonium block were not reversible. Another compound malouétine that was a bis-quaternary steroid was isolated from the plant Malouetia bequaertiana and showed curariform activity. This led to the synthetic drug pancuronium, a bis-quaternary steroid, and subsequently other drugs that had better pharmacological properties. Research on these molecules helped improve understanding of the physiology of neurons and receptors.

Neurochemistry

Latia luciferin is, in terms of chemistry, (E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohex-1-yl)-1-buten-1-ol formate and is from the freshwater snail Latia neritoides.

Bioluminescence