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=== Neurotransmitter ===
=== Neurotransmitter ===


In [[vertebrates]], GABA acts at inhibitory [[synapse]]s in the [[brain]] by binding to specific transmembrane [[Receptor (biochemistry)|receptor]]s in the [[plasma membrane]] of both pre- and postsynaptic neuronal processes. This binding causes the opening of [[ion channel]]s to allow the flow of either negatively charged [[chloride]] ions into the [[cell (biology)|cell]] or positively charged [[potassium]] ions out of the cell. This action results in a negative change in the [[transmembrane potential]], usually causing [[hyperpolarization (biology)|hyperpolarization]]. Three general classes of [[GABA receptor]] are known: [[GABA A receptor|GABA<sub><small>A</small></sub>]], which is an ion channels, and [[GABA B receptor|GABA<sub><small>B</small></sub>]] [[metabotropic receptor]]s, which are [[G protein-coupled receptor]]s that open or close ion channels via intermediaries ([[G protein]]s).
In [[vertebrates]], GABA acts at inhibitory [[synapse]]s in the [[brain]] by binding to specific transmembrane [[Receptor (biochemistry)|receptor]]s in the [[plasma membrane]] of both pre- and postsynaptic neuronal processes. This binding causes the opening of [[ion channel]]s to allow the flow of either negatively charged [[chloride]] ions into the [[cell (biology)|cell]] or positively charged [[potassium]] ions out of the cell. This action results in a negative change in the [[transmembrane potential]], usually causing [[hyperpolarization (biology)|hyperpolarization]]. Two general classes of [[GABA receptor]] are known: [[GABA A receptor|GABA<sub><small>A</small></sub>]], which is an ion channels, and [[GABA B receptor|GABA<sub><small>B</small></sub>]] [[metabotropic receptor]]s, which are [[G protein-coupled receptor]]s that open or close ion channels via intermediaries ([[G protein]]s).


Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. [[Medium spiny neuron|Medium Spiny Cells]] are a typical example of inhibitory [[Central nervous system|CNS]] GABAergic cells. In contrast, GABA exhibits excitatory actions in [[insect]]s, mediating [[muscle]] activation at synapses between [[nerve]]s and muscle cells, and also the stimulation of certain [[gland]]s.
Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. [[Medium spiny neuron|Medium Spiny Cells]] are a typical example of inhibitory [[Central nervous system|CNS]] GABAergic cells. In contrast, GABA exhibits excitatory actions in [[insect]]s, mediating [[muscle]] activation at synapses between [[nerve]]s and muscle cells, and also the stimulation of certain [[gland]]s.

Revision as of 21:22, 18 May 2009

"GABA" redirects here. For other uses, see GABA (disambiguation).
gamma-Aminobutyric acid
Names
IUPAC name
4-aminobutanoic acid
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.000.235 Edit this at Wikidata
MeSH gamma-Aminobutyric+Acid
  • C(CC(=O)O)CN
Properties
C4H9NO2
Molar mass 103.12 g/mol
Melting point 203.7 °C (398.7 °F; 476.8 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

γ-Aminobutyric acid (GABA) (IPA: [ˈgæmˌə əˈmiːˌnoː byuːˈtæəˌrɨc ˈæˌsɨd]) is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays an important role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.[1] In insect species GABA acts only on excitatory nerve receptors.

While technically an amino acid, GABA is rarely referred to as such in the scientific or medical communities, because the term "amino acid," used without a qualifier, refers to the alpha amino acids, which GABA is not, nor is it incorporated into proteins.

In spastic diplegia in humans, GABA absorption by some nerves becomes damaged, which leads to hypertonia of the muscles signaled by those nerves.

Function

Neurotransmitter

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: GABAA, which is an ion channels, and GABAB metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).

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 CNS GABAergic cells. In contrast, GABA exhibits excitatory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands.

GABAA receptors are chloride channels, that is, when activated by GABA, they allow the flow of chloride ions across the membrane of the cell. Whether this chloride flow is excitatory/depolarizing (makes the voltage across the cells membrane less negative), shunting (has no effect on the cells membrane) or inhibitory/hyperpolarizing (makes the cells membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is excitatory or depolarizing; when the net 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 minimises the effect any coincident synaptic input essentially by reducing the electrical resistance of the cell's membrane (essentially equivilint to Ohms law). A developmental switch in the molecular machinery controlling concentration of chloride inside the cell and hence the direction of this ion flow, is responsible for the changes in the functional role of GABA between the neonatal and adult stages. That is to say, GABA's role changes from excitatory to inhibitory as the brain develops into adulthood.[2]

Development

In hippocampus and neocortex of the mammalian brain, GABA has primarily excitatory effects early in development, and is in fact the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamate synapses - See developing cortex.[2]

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) paracrine (acting on nearby cells) signalling mediator.[3][4]

GABA regulates the proliferation of neural progenitor cells[5][6] the migration[7] and differentiation[8][9] the elongation of neurites[10] and the formation of synapses.[11]

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.[12] GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.[13]

Structure and conformation

GABA is found mostly as a zwitterion, that is, 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 because of the electrostatic attraction between the two functional groups. The stabilization is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, a more 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.[14][15]

History

Gamma-aminobutyric acid was first synthesized in 1883, and was first known only as a plant and microbe metabolic product. In 1950, however, GABA was discovered to be an integral part of the mammalian central nervous system.[16]

Synthesis

Organisms synthesize GABA from glutamate using the enzyme L-glutamic acid decarboxylase and pyridoxal phosphate (which is the active form of B6) as a cofactor. This process converts the principal excitatory neurotransmitter (glutamate) into the principal inhibitory one (GABA).[17][18]

Pharmacology

Drugs that act as agonists 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.[19] Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.

It has been suggested that orally administered GABA increases the amount of Human Growth Hormone, but this is questionable since it is unknown whether GABA can pass the blood-brain barrier. However, orally administered GABA does have effects outside of the central nervous system (e.g. decreased muscle tone).[citation needed]

Examples of GABAergic Drugs

See also

References

  1. ^ Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H (2002). "GABA and GABA receptors in the central nervous system and other organs". Int. Rev. Cytol. 213: 1–47. PMID 11837891.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b Li K, Xu E (2008). "The role and the mechanism of gamma-aminobutyric acid during central nervous system development". Neurosci Bull. 24 (3): 195–200. PMID 18500393. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ^ Purves D, Fitzpatrick D, Hall WC, Augustine GJ, Lamantia A-S (2007). Neuroscience (4th ed.). Sunderland, Mass: Sinauer. pp. 135, box 6D. ISBN 0-87893-697-1.{{cite book}}: CS1 maint: multiple names: authors list (link)
  4. ^ Jelitai M, Madarasz E (2005). "The role of GABA in the early neuronal development" (PDF). Int. Rev. Neurobiol. 71: 27–62. doi:10.1016/S0074-7742(05)71002-3. PMID 16512345.
  5. ^ LoTurco JJ, Owens DF, Heath MJ, Davis MB, Kriegstein AR (1995). "GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis". Neuron. 15 (6): 1287–98. doi:10.1016/0896-6273(95)90008-X. PMID 8845153. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Haydar TF, Wang F, Schwartz ML, Rakic P (2000). "Differential modulation of proliferation in the neocortical ventricular and subventricular zones". J. Neurosci. 20 (15): 5764–74. PMID 10908617. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Behar TN, Schaffner AE, Scott CA, O'Connell C, Barker JL (1998). "Differential response of cortical plate and ventricular zone cells to GABA as a migration stimulus". J. Neurosci. 18 (16): 6378–87. PMID 9698329. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Barbin G, Pollard H, Gaïarsa JL, Ben-Ari Y (1993). "Involvement of GABAA receptors in the outgrowth of cultured hippocampal neurons". Neurosci. Lett. 152 (1–2): 150–4. doi:10.1016/0304-3940(93)90505-F. PMID 8390627. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Ganguly K, Schinder AF, Wong ST, Poo M (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Maric D, Liu QY, Maric I, Chaudry S, Chang YH, Smith SV, Sieghart W, Fritschy JM, Barker JL (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. PMID 11264309. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Ben-Ari Y (2002). "Excitatory actions of gaba during development: the nature of the nurture". Nat. Rev. Neurosci. 3 (9): 728–39. doi:10.1038/nrn920. PMID 12209121. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ Obrietan K, Gao XB, Van Den Pol AN (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. PMID 12163549. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Wang DD, Kriegstein AR, Ben-Ari Y (2008). "GABA Regulates Stem Cell Proliferation before Nervous System Formation". Epilepsy currents / American Epilepsy Society. 8 (5): 137–9. doi:10.1111/j.1535-7511.2008.00270.x. PMC 2566617. PMID 18852839.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Devashis Majumdar and Sephali Guha. Conformation, electrostatic potential and pharmacophoric pattern of GABA (gamma-aminobutyric acid) and several GABA inhibitors. Journal of Molecular Structure: THEOCHEM 1988, 180, 125-140. doi:10.1016/0166-1280(88)80084-8
  15. ^ Anne-Marie Sapse. Molecular Orbital Calculations for Amino Acids and Peptides. Birkhäuser, 2000. ISBN 0817638938.
  16. ^ Roth, Robert J.; Cooper, Jack R.; Bloom, Floyd E. (2003). The Biochemical Basis of Neuropharmacology. Oxford [Oxfordshire]: Oxford University Press. pp. 416 pages. ISBN 0-19-514008-7.{{cite book}}: CS1 maint: multiple names: authors list (link)
  17. ^ Petroff OA (2002). "GABA and glutamate in the human brain". Neuroscientist. 8 (6): 562–73. PMID 12467378. {{cite journal}}: Unknown parameter |month= ignored (help)
  18. ^ Schousboe A, Waagepetersen HS (2007). "GABA: homeostatic and pharmacological aspects". Prog. Brain Res. 160: 9–19. doi:10.1016/S0079-6123(06)60002-2. PMID 17499106.
  19. ^ Foster AC, Kemp JA (2006). "Glutamate- and GABA-based CNS therapeutics". Curr Opin Pharmacol. 6 (1): 7–17. doi:10.1016/j.coph.2005.11.005. PMID 16377242. {{cite journal}}: Unknown parameter |month= ignored (help)
  20. ^ Dzitoyeva S, Dimitrijevic N, Manev H (2003). "Gamma-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): 5485–90. doi:10.1073/pnas.0830111100. PMID 12692303.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ 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): 385–9. doi:10.1038/38738. PMID 9311780.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Boehm SL, Ponomarev I, Blednov YA, Harris RA (2006). "From gene to behavior and back again: new perspectives on GABAA receptor subunit selectivity of alcohol actions". Adv. Pharmacol. 54: 171–203. doi:10.1016/j.bcp.2004.07.023. PMID 17175815.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ 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): 246–52. doi:10.1016/j.ejphar.2005.07.016. PMID 16129424.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Lydiard B, Pollack MH, Ketter TA, Kisch E, Hettema JM (2001-10-26). "GABA". Continuing Medical Education. School of Medicine, Virginia Commonwealth University, Medical College of Virginia Campus (VCU), Richmond, VA. Retrieved 2008-06-20. The role of GABA in the pathogenesis and treatment of anxiety and other neuropsychiatric disorders {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)CS1 maint: multiple names: authors list (link)
  • Scholarpedia article on GABA
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