gamma-Aminobutyric acid, or γ-aminobutyric acid /ˈɡæmə əˈmnbjuːˈtɪrɪk ˈæsɪd/, or GABA /ˈɡæbə/, is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.[2]

gamma-Aminobutyric acid
Simplified structural formula
GABA molecule
Names
Preferred IUPAC name
4-Aminobutanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.235
EC Number 200-258-6
KEGG
MeSH gamma-Aminobutyric+Acid
RTECS number ES6300000
UNII
Properties
C4H9NO2
Molar mass 103.120 g/mol
Appearance white microcrystalline powder
Density 1.11 g/mL
Melting point 203.7 °C (398.7 °F; 476.8 K)
Boiling point 247.9 °C (478.2 °F; 521.0 K)
130 g/100 mL
log P −3.17
Acidity (pKa)
  • 4.031 (carboxyl; H2O)
  • 10.556 (amino; H2O)[1]
Hazards
Main hazards Irritant, Harmful
Lethal dose or concentration (LD, LC):
12,680 mg/kg (mouse, oral)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is ☑Y☒N ?)
Infobox references

GABA is sold as a dietary supplement.

Contents

FunctionEdit

NeurotransmitterEdit

 
GABA metabolism, involvement of glial cells

In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization. Two general classes of GABA receptor are known:[3]

 
The production, release, action, and degradation of GABA at a stereotyped GABAergic synapse

Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. Medium spiny cells are a typical example of inhibitory central nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands.[4] In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.[5]

GABAA receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow of chloride ions across the membrane of the cell. Whether this chloride flow is depolarizing (makes the voltage across the cell's membrane less negative), shunting (has no effect on the cell's membrane potential), or inhibitory/hyperpolarizing (makes the cell's membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when chloride flows into the cell, GABA is inhibitory or hyperpolarizing. When the net flow of chloride is close to zero, the action of GABA is shunting. Shunting inhibition has no direct effect on the membrane potential of the cell; however, it reduces the effect of any coincident synaptic input by reducing the electrical resistance of the cell's membrane. Shunting inhibition can "override" the excitatory effect of depolarising GABA, resulting in overall inhibition even if the membrane potential becomes less negative. It was thought that a developmental switch in the molecular machinery controlling the concentration of chloride inside the cell changes the functional role of GABA between neonatal and adult stages. As the brain develops into adulthood, GABA's role changes from excitatory to inhibitory.[6]

Brain developmentEdit

While GABA is an inhibitory transmitter in the mature brain, its actions were thought to be primarily excitatory in the developing brain.[6][7] The gradient of chloride was reported to be reversed in immature neurons, with its reversal potential higher than the resting membrane potential of the cell; activation of a GABA-A receptor thus leads to efflux of Cl ions from the cell (that is, a depolarizing current). The differential gradient of chloride in immature neurons was shown to be primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABAergic interneurons mature faster in the hippocampus and the GABA signalling machinery appears earlier than glutamatergic transmission. Thus, GABA is considered the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamatergic synapses.[8]

In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an autocrine (acting on the same cell) and paracrine (acting on nearby cells) signalling mediator.[9][10] The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.[11]

GABA regulates the proliferation of neural progenitor cells[12][13] the migration[14] and differentiation[15][16] the elongation of neurites[17] and the formation of synapses.[18]

GABA also regulates the growth of embryonic and neural stem cells. GABA can influence the development of neural progenitor cells via brain-derived neurotrophic factor (BDNF) expression.[19] GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.[20]

Beyond the nervous systemEdit

 
mRNA expression of the embryonic variant of the GABA-producing enzyme GAD67 in a coronal brain section of a one-day-old Wistar rat, with the highest expression in subventricular zone (svz)[21]

Besides the nervous system, GABA is also produced at relatively high levels in the insulin-producing β-cells of the pancreas. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighboring islet α-cells and inhibits them from secreting glucagon (which would counteract insulin’s effects).[22]

GABA can promote the replication and survival of β-cells[23][24][25] and also promote the conversion of α-cells to β-cells, which may lead to new treatments for diabetes.[26]

GABA has also been detected in other peripheral tissues including intestines, stomach, Fallopian tubes, uterus, ovaries, testes, kidneys, urinary bladder, the lungs and liver, albeit at much lower levels than in neurons or β-cells. GABAergic mechanisms have been demonstrated in various peripheral tissues and organs, which include the intestines, the stomach, the pancreas, the Fallopian tubes, the uterus, the ovaries, the testes, the kidneys, the urinary bladder, the lungs, and the liver.[27]

Immune cells express receptors for GABA[28][29] and administration of GABA can suppress inflammatory immune responses and promote "regulatory" immune responses, such that GABA administration has been shown to inhibit autoimmune diseases in several animal models.[23][28][30][31]

In 2018, GABA has shown to regulate secretion of a greater number of cytokines. In plasma of T1D patients, levels of 26 cytokines are increased and of those, 16 are inhibited by GABA in the cell assays.[32]

In 2007, an excitatory GABAergic system was described in the airway epithelium. The system is activated by exposure to allergens and may participate in the mechanisms of asthma.[33] GABAergic systems have also been found in the testis[34] and in the eye lens.[35]

GABA occurs in plants.[36][37]

Structure and conformationEdit

GABA is found mostly as a zwitterion (i.e. with the carboxyl group deprotonated and the amino group protonated). Its conformation depends on its environment. In the gas phase, a highly folded conformation is strongly favored due to the electrostatic attraction between the two functional groups. The stabilization is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, an extended conformation is found, with a trans conformation at the amino end and a gauche conformation at the carboxyl end. This is due to the packing interactions with the neighboring molecules. In solution, five different conformations, some folded and some extended, are found as a result of solvation effects. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. Many GABA analogues with pharmaceutical applications have more rigid structures in order to control the binding better.[38][39]

HistoryEdit

In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product.[40]

In 1950, GABA was discovered as an integral part of the mammalian central nervous system.[40]

In 1959, it was shown that at an inhibitory synapse on crayfish muscle fibers GABA acts like stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked by picrotoxin.[41]

BiosynthesisEdit

 
GABAergic neurons which produce GABA

GABA is synthesized from glutamate via the enzyme glutamate decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor. This process converts glutamate (the principal excitatory neurotransmitter) into GABA (the principal inhibitory neurotransmitter).[42][43]

Traditionally it was thought that exogenous GABA did not penetrate the blood–brain barrier,[44] however more current research[45] indicates that it may be possible, or that exogenous GABA (i.e. in the form of nutritional supplements) could exert GABAergic effects on the enteric nervous system which in turn stimulate endogenous GABA production. The direct involvement of GABA in the glutamate–glutamine cycle makes the question of whether GABA can penetrate the blood-brain barrier somewhat misleading, because both glutamate and glutamine can freely cross the barrier and convert to GABA within the brain.

CatabolismEdit

GABA transaminase enzyme catalyzes the conversion of 4-aminobutanoic acid (GABA) and 2-oxoglutarate (α-ketoglutarate) into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy.[46]

PharmacologyEdit

Drugs that act as allosteric modulators of GABA receptors (known as GABA analogues or GABAergic drugs), or increase the available amount of GABA, typically have relaxing, anti-anxiety, and anti-convulsive effects.[47][48] Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.[49]

In general, GABA does not cross the blood–brain barrier,[44] although certain areas of the brain that have no effective blood–brain barrier, such as the periventricular nucleus, can be reached by drugs such as systemically injected GABA.[50] At least one study suggests that orally administered GABA increases the amount of human growth hormone (HGH).[51] GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual.[50] Certain pro-drugs of GABA (ex. picamilon) have been developed to permeate the blood–brain barrier, then separate into GABA and the carrier molecule once inside the brain. Prodrugs allow for a direct increase of GABA levels throughout all areas of the brain, in a manner following the distribution pattern of the pro-drug prior to metabolism.[citation needed]

GABA enhanced the catabolism of serotonin into N-acetylserotonin (the precursor of melatonin) in rats.[52] It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.[53]

ChemistryEdit

Although in chemical terms, GABA is an amino acid (as it has both a primary amine and a carboxylic acid functional group), it is rarely referred to as such in the professional, scientific, or medical community. By convention the term "amino acid", when used without a qualifier, refers specifically to an alpha amino acid. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon so it is not incorporated into proteins.[54]

GABAergic drugsEdit

GABAA receptor ligands are shown in the following table[nb 1]

Activity at GABAA Ligand
Orthosteric Agonist Muscimol,[55] GABA[55], gaboxadol (THIP),[55] isoguvacine, progabide, piperidine-4-sulfonic acid (partial agonist)
Positive allosteric modulators Barbiturates[56], benzodiazepines[57], neuroactive steroids[58] niacin/niacinamide,[59], nonbenzodiazepiness (i.e. z-drugs, e.g. zolpidem, eszopiclone)[citation needed], etomidate[60], etaqualone[citation needed], alcohol (ethanol),[61][62][63], theanine[citation needed], methaqualone, propofol, stiripentol,[64], and anaesthetics[55] (including volatile anaesthetics), glutethimide[citation needed]
Orthosteric (competive) Antagonist bicuculline[55], gabazine,[65] thujone[66], flumazenil[67]
Uncompetitive antagonist (e.g. channel blocker) picrotoxin[citation needed], cicutoxin
Negative allosteric modulators neuroactive steroids[citation needed] (Pregnenolone sulfate[citation needed]), furosemide, oenanthotoxin, amentoflavone

Additionally, carisoprodol is an enhancer GABAA activity[citation needed]. Ro15-4513 is a reducer of GABAA activity[citation needed].

GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol[68], which then acts via the GABAA receptor.[69]

skullcap and valerian are plants containing GABAergic substances[citation needed]. Furthermore, the plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.[70]

Other GABAergic modulators include:

In plantsEdit

GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes.[74] Evidence also suggests a role in cell signalling in plants.[75][76]

See alsoEdit

NotesEdit

  1. ^ Many more GABAA ligands are listed at Template:GABA_receptor_modulators and at GABAA receptor#Ligands

ReferencesEdit

  1. ^ Haynes, William M., ed. (2016). CRC Handbook of Chemistry and Physics (97th ed.). CRC Press. p. 5–88. ISBN 978-1498754286.
  2. ^ Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H (2002). "GABA and GABA receptors in the central nervous system and other organs". In Jeon KW (ed.). Int. Rev. Cytol. International Review of Cytology. 213. pp. 1–47. doi:10.1016/S0074-7696(02)13011-7. ISBN 978-0-12-364617-0. PMID 11837891.
  3. ^ Generalized Non-Convulsive Epilepsy: Focus on GABA-B Receptors, C. Marescaux, M. Vergnes, R. Bernasconi
  4. ^ Ffrench-Constant RH, Rocheleau TA, Steichen JC, Chalmers AE (June 1993). "A point mutation in a Drosophila GABA receptor confers insecticide resistance". Nature. 363 (6428): 449–51. Bibcode:1993Natur.363..449F. doi:10.1038/363449a0. PMID 8389005.
  5. ^ Szabadics J, Varga C, Molnár G, Oláh S, Barzó P, Tamás G (January 2006). "Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits". Science. 311 (5758): 233–235. Bibcode:2006Sci...311..233S. doi:10.1126/science.1121325. PMID 16410524.
  6. ^ a b Li K, Xu E (June 2008). "The role and the mechanism of γ-aminobutyric acid during central nervous system development". Neurosci Bull. 24 (3): 195–200. doi:10.1007/s12264-008-0109-3. PMC 5552538. PMID 18500393.
  7. ^ Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R (October 2007). "GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations". Physiol. Rev. 87 (4): 1215–1284. doi:10.1152/physrev.00017.2006. PMID 17928584.
  8. ^ The Glutamate/GABA-Glutamine Cycle: Amino Acid Neurotransmitter Homeostasis, Arne Schousboe, Ursula Sonnewald
  9. ^ Purves D, Fitzpatrick D, Hall WC, Augustine GJ, Lamantia AS, eds. (2007). Neuroscience (4th ed.). Sunderland, Mass: Sinauer. pp. 135, box 6D. ISBN 978-0-87893-697-7.
  10. ^ Jelitai M, Madarasz E (2005). The role of GABA in the early neuronal development. Int. Rev. Neurobiol. International Review of Neurobiology. 71. pp. 27–62. doi:10.1016/S0074-7742(05)71002-3. ISBN 9780123668721. PMID 16512345.
  11. ^ Marín O, Rubenstein JL (November 2001). "A long, remarkable journey: tangential migration in the telencephalon". Nat. Rev. Neurosci. 2 (11): 780–90. doi:10.1038/35097509. PMID 11715055.
  12. ^ LoTurco JJ, Owens DF, Heath MJ, Davis MB, Kriegstein AR (December 1995). "GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis". Neuron. 15 (6): 1287–1298. doi:10.1016/0896-6273(95)90008-X. PMID 8845153.
  13. ^ Haydar TF, Wang F, Schwartz ML, Rakic P (August 2000). "Differential modulation of proliferation in the neocortical ventricular and subventricular zones". J. Neurosci. 20 (15): 5764–74. doi:10.1523/JNEUROSCI.20-15-05764.2000. PMC 3823557. PMID 10908617.
  14. ^ Behar TN, Schaffner AE, Scott CA, O'Connell C, Barker JL (August 1998). "Differential response of cortical plate and ventricular zone cells to GABA as a migration stimulus". J. Neurosci. 18 (16): 6378–87. doi:10.1523/JNEUROSCI.18-16-06378.1998. PMID 9698329.
  15. ^ Ganguly K, Schinder AF, Wong ST, Poo M (May 2001). "GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition". Cell. 105 (4): 521–32. doi:10.1016/S0092-8674(01)00341-5. PMID 11371348.
  16. ^ Barbin G, Pollard H, Gaïarsa JL, Ben-Ari Y (April 1993). "Involvement of GABAA receptors in the outgrowth of cultured hippocampal neurons". Neurosci. Lett. 152 (1–2): 150–154. doi:10.1016/0304-3940(93)90505-F. PMID 8390627.
  17. ^ Maric D, Liu QY, Maric I, Chaudry S, Chang YH, Smith SV, Sieghart W, Fritschy JM, Barker JL (April 2001). "GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl channels". J. Neurosci. 21 (7): 2343–60. doi:10.1523/JNEUROSCI.21-07-02343.2001. PMID 11264309.
  18. ^ Ben-Ari Y (September 2002). "Excitatory actions of gaba during development: the nature of the nurture". Nat. Rev. Neurosci. 3 (9): 728–739. doi:10.1038/nrn920. PMID 12209121.
  19. ^ Obrietan K, Gao XB, Van Den Pol AN (August 2002). "Excitatory actions of GABA increase BDNF expression via a MAPK-CREB-dependent mechanism—a positive feedback circuit in developing neurons". J. Neurophysiol. 88 (2): 1005–15. doi:10.1152/jn.2002.88.2.1005. PMID 12163549.
  20. ^ Wang DD, Kriegstein AR, Ben-Ari Y (2008). "GABA regulates stem cell proliferation before nervous system formation". Epilepsy Curr. 8 (5): 137–9. doi:10.1111/j.1535-7511.2008.00270.x. PMC 2566617. PMID 18852839.
  21. ^ Popp A, Urbach A, Witte OW, Frahm C (2009). Reh TA (ed.). "Adult and embryonic GAD transcripts are spatiotemporally regulated during postnatal development in the rat brain". PLoS ONE. 4 (2): e4371. Bibcode:2009PLoSO...4.4371P. doi:10.1371/journal.pone.0004371. PMC 2629816. PMID 19190758.
  22. ^ Rorsman P, Berggren PO, Bokvist K, Ericson H, Möhler H, Ostenson CG, Smith PA (1989). "Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels". Nature. 341 (6239): 233–6. Bibcode:1989Natur.341..233R. doi:10.1038/341233a0. PMID 2550826.
  23. ^ a b Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud'homme GJ, Wang Q (2011). "GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes". Proc. Natl. Acad. Sci. U.S.A. 108 (28): 11692–7. Bibcode:2011PNAS..10811692S. doi:10.1073/pnas.1102715108. PMC 3136292. PMID 21709230.
  24. ^ Tian J, Dang H, Chen Z, Guan A, Jin Y, Atkinson MA, Kaufman DL (2013). "γ-Aminobutyric acid regulates both the survival and replication of human β-cells". Diabetes. 62 (11): 3760–5. doi:10.2337/db13-0931. PMC 3806626. PMID 23995958.
  25. ^ Purwana I, Zheng J, Li X, Deurloo M, Son DO, Zhang Z, Liang C, Shen E, Tadkase A, Feng ZP, Li Y, Hasilo C, Paraskevas S, Bortell R, Greiner DL, Atkinson M, Prud'homme GJ, Wang Q (2014). "GABA promotes human β-cell proliferation and modulates glucose homeostasis". Diabetes. 63 (12): 4197–205. doi:10.2337/db14-0153. PMID 25008178.
  26. ^ Ben-Othman N, Vieira A, Courtney M, Record F, Gjernes E, Avolio F, Hadzic B, Druelle N, Napolitano T, Navarro-Sanz S, Silvano S, Al-Hasani K, Pfeifer A, Lacas-Gervais S, Leuckx G, Marroquí L, Thévenet J, Madsen OD, Eizirik DL, Heimberg H, Kerr-Conte J, Pattou F, Mansouri A, Collombat P (2017). "Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis". Cell. 168 (1–2): 73–85.e11. doi:10.1016/j.cell.2016.11.002. PMID 27916274.
  27. ^ Erdö SL, Wolff JR (February 1990). "γ-Aminobutyric acid outside the mammalian brain". J. Neurochem. 54 (2): 363–72. doi:10.1111/j.1471-4159.1990.tb01882.x. PMID 2405103.
  28. ^ a b Tian J, Chau C, Hales TG, Kaufman DL (1999). "GABAA receptors mediate inhibition of T cell responses". J. Neuroimmunol. 96 (1): 21–8. doi:10.1016/s0165-5728(98)00264-1. PMID 10227421.
  29. ^ Mendu SK, Bhandage A, Jin Z, Birnir B (2012). "Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes". PLoS ONE. 7 (8): e42959. Bibcode:2012PLoSO...742959M. doi:10.1371/journal.pone.0042959. PMC 3424250. PMID 22927941.
  30. ^ Tian J, Lu Y, Zhang H, Chau CH, Dang HN, Kaufman DL (2004). "Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model". J. Immunol. 173 (8): 5298–304. doi:10.4049/jimmunol.173.8.5298. PMID 15470076.
  31. ^ Tian J, Yong J, Dang H, Kaufman DL (2011). "Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis". Autoimmunity. 44 (6): 465–70. doi:10.3109/08916934.2011.571223. PMC 5787624. PMID 21604972.
  32. ^ Bhandage AK, Jin Z, Korol SV, Shen Q, Pei Y, Deng Q, Espes D, Carlsson PO, Kamali-Moghaddam M, Birnir B (April 2018). "+ T Cells and Is Immunosuppressive in Type 1 Diabetes". EBioMedicine. 30: 283–294. doi:10.1016/j.ebiom.2018.03.019. PMC 5952354. PMID 29627388.
  33. ^ Xiang YY, Wang S, Liu M, Hirota JA, Li J, Ju W, Fan Y, Kelly MM, Ye B, Orser B, O'Byrne PM, Inman MD, Yang X, Lu WY (July 2007). "A GABAergic system in airway epithelium is essential for mucus overproduction in asthma". Nat. Med. 13 (7): 862–7. doi:10.1038/nm1604. PMID 17589520.
  34. ^ Payne AH, Hardy MH (2007). The Leydig cell in health and disease. Humana Press. ISBN 978-1-58829-754-9.
  35. ^ Kwakowsky A, Schwirtlich M, Zhang Q, Eisenstat DD, Erdélyi F, Baranyi M, Katarova ZD, Szabó G (December 2007). "GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: correlation with Dlx2 and Dlx5". Dev. Dyn. 236 (12): 3532–44. doi:10.1002/dvdy.21361. PMID 17969168.
  36. ^ Ramesh SA, Tyerman SD, Xu B, Bose J, Kaur S, Conn V, Domingos P, Ullah S, Wege S, Shabala S, Feijó JA, Ryan PR, Gilliham M, Gillham M (2015). "GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters". Nat Commun. 6: 7879. Bibcode:2015NatCo...6E7879R. doi:10.1038/ncomms8879. PMC 4532832. PMID 26219411.
  37. ^ Ramesh SA, Tyerman SD, Gilliham M, Xu B (2016). "γ-Aminobutyric acid (GABA) signalling in plants". Cell. Mol. Life Sci. 74 (9): 1577–1603. doi:10.1007/s00018-016-2415-7. PMID 27838745.
  38. ^ Majumdar D, Guha S (1988). "Conformation, electrostatic potential and pharmacophoric pattern of GABA (γ-aminobutyric acid) and several GABA inhibitors". Journal of Molecular Structure: THEOCHEM. 180: 125–140. doi:10.1016/0166-1280(88)80084-8.
  39. ^ Sapse AM (2000). Molecular Orbital Calculations for Amino Acids and Peptides. Birkhäuser. ISBN 978-0-8176-3893-1.[page needed]
  40. ^ a b Roth RJ, Cooper JR, Bloom FE (2003). The Biochemical Basis of Neuropharmacology. Oxford [Oxfordshire]: Oxford University Press. p. 106. ISBN 978-0-19-514008-8.
  41. ^ W. G. Van der Kloot; J. Robbins (1959). "The effects of GABA and picrotoxin on the junctional potential and the contraction of crayfish muscle". Experientia. 15: 36.
  42. ^ Petroff OA (December 2002). "GABA and glutamate in the human brain". Neuroscientist. 8 (6): 562–573. doi:10.1177/1073858402238515. PMID 12467378.
  43. ^ Schousboe A, Waagepetersen HS (2007). GABA: homeostatic and pharmacological aspects. Prog. Brain Res. Progress in Brain Research. 160. pp. 9–19. doi:10.1016/S0079-6123(06)60002-2. ISBN 978-0-444-52184-2. PMID 17499106.
  44. ^ a b Kuriyama K, Sze PY (January 1971). "Blood–brain barrier to H3-γ-aminobutyric acid in normal and amino oxyacetic acid-treated animals". Neuropharmacology. 10 (1): 103–108. doi:10.1016/0028-3908(71)90013-X. PMID 5569303.
  45. ^ Boonstra E, de Kleijn R, Colzato LS, Alkemade A, Forstmann BU, Nieuwenhuis S (2015). "Neurotransmitters as food supplements: the effects of GABA on brain and behavior". Front Psychol. 6: 1520. doi:10.3389/fpsyg.2015.01520. PMC 4594160. PMID 26500584.
  46. ^ Bown AW, Shelp BJ (September 1997). "The Metabolism and Functions of γ-Aminobutyric Acid". Plant Physiol. 115 (1): 1–5. doi:10.1104/pp.115.1.1. PMC 158453. PMID 12223787.
  47. ^ Foster AC, Kemp JA (February 2006). "Glutamate- and GABA-based CNS therapeutics". Curr Opin Pharmacol. 6 (1): 7–17. doi:10.1016/j.coph.2005.11.005. PMID 16377242.
  48. ^ Chapouthier G, Venault P (October 2001). "A pharmacological link between epilepsy and anxiety?". Trends Pharmacol. Sci. 22 (10): 491–3. doi:10.1016/S0165-6147(00)01807-1. PMID 11583788.
  49. ^ Campagna JA, Miller KW, Forman SA (May 2003). "Mechanisms of actions of inhaled anesthetics". N. Engl. J. Med. 348 (21): 2110–24. doi:10.1056/NEJMra021261. PMID 12761368.
  50. ^ a b Müller EE, Locatelli V, Cocchi D (April 1999). "Neuroendocrine control of growth hormone secretion". Physiol. Rev. 79 (2): 511–607. doi:10.1152/physrev.1999.79.2.511. PMID 10221989.
  51. ^ Powers ME, Yarrow JF, McCoy SC, Borst SE (January 2008). "Growth hormone isoform responses to GABA ingestion at rest and after exercise". Medicine and Science in Sports and Exercise. 40 (1): 104–10. doi:10.1249/mss.0b013e318158b518. PMID 18091016.
  52. ^ Balemans MG, Mans D, Smith I, Van Benthem J (1983). "The influence of GABA on the synthesis of N-acetylserotonin, melatonin, O-acetyl-5-hydroxytryptophol and O-acetyl-5-methoxytryptophol in the pineal gland of the male Wistar rat". Reproduction, Nutrition, Development. 23 (1): 151–60. doi:10.1051/rnd:19830114. PMID 6844712.
  53. ^ Sato S, Yinc C, Teramoto A, Sakuma Y, Kato M (2008). "Sexually dimorphic modulation of GABA(A) receptor currents by melatonin in rats gonadotropin–releasing hormone neurons". J Physiol Sci. 58 (5): 317–322. doi:10.2170/physiolsci.rp006208. PMID 18834560.
  54. ^ The Brain, the Nervous System, and Their Diseases [3 volumes], Jennifer L. Hellier
  55. ^ a b c d e Chua HC, Chebib M (2017). GABAA Receptors and the Diversity in their Structure and Pharmacology. Advances in Pharmacology (San Diego, Calif.). Advances in Pharmacology. 79. pp. 1–34. doi:10.1016/bs.apha.2017.03.003. ISBN 9780128104132. PMID 28528665.
  56. ^ Löscher, W.; Rogawski, M. A. (2012). "How theories evolved concerning the mechanism of action of barbiturates". Epilepsia. 53: 12–25. doi:10.1111/epi.12025. PMID 23205959.
  57. ^ Olsen RW, Betz H (2006). "GABA and glycine". In Siegel GJ, Albers RW, Brady S, Price DD (eds.). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (7th ed.). Elsevier. pp. 291–302. ISBN 978-0-12-088397-4.
  58. ^ (a) Herd MB, Belelli D, Lambert JJ (October 2007). "Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors". Pharmacology & Therapeutics. 116 (1): 20–34. doi:10.1016/j.pharmthera.2007.03.007. PMID 17531325.; (b) Hosie AM, Wilkins ME, da Silva HM, Smart TG (November 2006). "Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites". Nature. 444 (7118): 486–9. doi:10.1038/nature05324. PMID 17108970.; (c)Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (September 2006). "Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis". Proceedings of the National Academy of Sciences of the United States of America. 103 (39): 14602–7. doi:10.1073/pnas.0606544103. PMC 1600006. PMID 16984997.; (d) Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (December 2005). "Neurosteroid access to the GABAA receptor". The Journal of Neuroscience. 25 (50): 11605–13. doi:10.1523/JNEUROSCI.4173-05.2005. PMID 16354918.; (e) Belelli D, Lambert JJ (July 2005). "Neurosteroids: endogenous regulators of the GABA(A) receptor". Nature Reviews. Neuroscience. 6 (7): 565–75. doi:10.1038/nrn1703. PMID 15959466.; (f) Pinna G, Costa E, Guidotti A (June 2006). "Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake". Psychopharmacology. 186 (3): 362–72. doi:10.1007/s00213-005-0213-2. PMID 16432684.; (g) Dubrovsky BO (February 2005). "Steroids, neuroactive steroids and neurosteroids in psychopathology". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 29 (2): 169–92. doi:10.1016/j.pnpbp.2004.11.001. PMID 15694225.; (h) Mellon SH, Griffin LD (2002). "Neurosteroids: biochemistry and clinical significance". Trends in Endocrinology and Metabolism. 13 (1): 35–43. doi:10.1016/S1043-2760(01)00503-3. PMID 11750861.; (i) Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E (May 1990). "Neurosteroids act on recombinant human GABAA receptors". Neuron. 4 (5): 759–65. doi:10.1016/0896-6273(90)90202-Q. PMID 2160838.; (j) Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (May 1986). "Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor". Science. 232 (4753): 1004–7. doi:10.1126/science.2422758. PMID 2422758.; (k) Reddy DS, Rogawski MA (2012). "Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy". In Noebels JL, Avoli M, Rogawski MA, et al. (eds.). Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US).
  59. ^ Toraskar, Mrunmayee; Pratima R.P. Singh; Shashank Neve (2010). "STUDY OF GABAERGIC AGONISTS" (PDF). Deccan Journal of Pharmacology. 1 (2): 56–69.
  60. ^ Vanlersberghe, C; Camu, F (2008). "Etomidate and other non-barbiturates". Handbook of Experimental Pharmacology. Handbook of Experimental Pharmacology. 182 (182): 267–82. doi:10.1007/978-3-540-74806-9_13. ISBN 978-3-540-72813-9. PMID 18175096.
  61. ^ Dzitoyeva S, Dimitrijevic N, Manev H (2003). "γ-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila: adult RNA interference and pharmacological evidence". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5485–5490. Bibcode:2003PNAS..100.5485D. doi:10.1073/pnas.0830111100. PMC 154371. PMID 12692303.
  62. ^ Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA, Harrison NL (1997). "Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors". Nature. 389 (6649): 385–389. Bibcode:1997Natur.389..385M. doi:10.1038/38738. PMID 9311780.
  63. ^ Boehm SL, Ponomarev I, Blednov YA, Harris RA (2006). "From gene to behavior and back again: new perspectives on GABAAreceptor subunit selectivity of alcohol actions". Adv. Pharmacol. 54 (8): 1581–1602. doi:10.1016/j.bcp.2004.07.023. PMID 17175815.
  64. ^ Fisher JL (January 2009). "The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator". Neuropharmacology. 56 (1): 190–7. doi:10.1016/j.neuropharm.2008.06.004. PMC 2665930. PMID 18585399.
  65. ^ Ueno, S; Bracamontes, J; Zorumski, C; Weiss, DS; Steinbach, JH (1997). "Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor". The Journal of Neuroscience. 17 (2): 625–34. PMID 8987785.
  66. ^ Olsen RW (April 2000). "Absinthe and gamma-aminobutyric acid receptors". Proc. Natl. Acad. Sci. U.S.A. 97 (9): 4417–8. doi:10.1073/pnas.97.9.4417. PMC 34311. PMID 10781032.
  67. ^ Whitwam, J. G.; Amrein, R. (1995-01-01). "Pharmacology of flumazenil". Acta Anaesthesiologica Scandinavica. Supplementum. 108: 3–14. ISSN 0515-2720. PMID 8693922.
  68. ^ Jira, Reinhard; Kopp, Erwin; McKusick, Blaine C.; Röderer, Gerhard; Bosch, Axel; Fleischmann, Gerald, "Chloroacetaldehydes", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a06_527.pub2
  69. ^ Lu, J.; Greco, M. A. (2006). "Sleep circuitry and the hypnotic mechanism of GABAA drugs". Journal of Clinical Sleep Medicine. 2 (2): S19–S26. PMID 17557503.
  70. ^ Singh YN, Singh NN (2002). "Therapeutic potential of kava in the treatment of anxiety disorders". CNS Drugs. 16 (11): 731–43. doi:10.2165/00023210-200216110-00002. PMID 12383029.
  71. ^ Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H (2005). "Drosophila GABAB receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB)". Eur. J. Pharmacol. 519 (3): 246–252. doi:10.1016/j.ejphar.2005.07.016. PMID 16129424.
  72. ^ Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT (August 2009). "Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity". Phytother Res. 23 (8): 1075–81. doi:10.1002/ptr.2712. PMID 19165747.
  73. ^ Celikyurt IK, Mutlu O, Ulak G, Akar FY, Erden F (2011). "Gabapentin, A GABA analogue, enhances cognitive performance in mice". Neuroscience Letters. 492 (2): 124–8. Bibcode:2006NeuL..400..197D. doi:10.1016/j.neulet.2011.01.072. PMID 21296127.
  74. ^ Park DH, Mirabella R, Bronstein PA, Preston GM, Haring MA, Lim CK, Collmer A, Schuurink RC (October 2010). "Mutations in γ-aminobutyric acid (GABA) transaminase genes in plants or Pseudomonas syringae reduce bacterial virulence". Plant J. 64 (2): 318–30. doi:10.1111/j.1365-313X.2010.04327.x. PMID 21070411.
  75. ^ Bouché N, Fromm H (March 2004). "GABA in plants: just a metabolite?". Trends Plant Sci. 9 (3): 110–5. doi:10.1016/j.tplants.2004.01.006. PMID 15003233.
  76. ^ Roberts MR (September 2007). "Does GABA Act as a Signal in Plants?: Hints from Molecular Studies". Plant Signal Behav. 2 (5): 408–9. doi:10.4161/psb.2.5.4335. PMC 2634229. PMID 19704616.

BibliographyEdit

External linksEdit