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GABA

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Template:Chembox new Gamma-aminobutyric acid (GABA) 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. 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

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. Three general classes of GABA receptor are known: GABAA and GABAC ionotropic receptors, which are ion channels themselves, and GABAB metabotropic receptors, which are G protein-coupled receptors that open 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 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.

GABA also regulates the growth of embryonic and neural stem cells. GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.[1]

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

Whether GABA is excitatory or inhibitory depends on the direction (into or out of the cell) and magnitude of the ionic currents controlled by the GABAA receptor. When net positive ionic current is directed into the cell, GABA is excitatory, when the net positive current is directed out of the cell, GABA is inhibitory. A developmental switch in the molecular machinery controlling the polarity of this current 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.

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.[2][3]

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.[4]

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).

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. Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.

GABA has been purported to increase the amount of the Human Growth Hormone. The results of those studies have been seldom replicated, and have recently been in question since it is unknown whether GABA can pass the blood-brain barrier.[citation needed]

Drugs that affect GABA receptors:

Drugs that affect GABA in other ways:

  • tiagabine—potentiates by inhibiting uptake into neurons and glia
  • vigabatrin—potentiates by inhibiting GABA-T, preventing GABA breakdown
  • valproate—potentiates by inhibiting GABA-T
  • tetanospasmin—primary toxin of tetanus bacteria, blocks release of GABA
  • hyperforin—inhibits the reuptake of GABA
  • thujone-A main ingredient in absinthe

See also

References

  1. ^ 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)
  2. ^ 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
  3. ^ Anne-Marie Sapse. Molecular Orbital Calculations for Amino Acids and Peptides. Birkhäuser, 2000. ISBN 0817638938.
  4. ^ 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)
  5. ^ 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)
  6. ^ 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)
  7. ^ 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)
  8. ^ a b Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.
  9. ^ Granger P, Biton B, Faure C, Vige X, Depoortere H, Graham D, Langer SZ, Scatton B, Avenet P (1995). "Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin". Mol. Pharmacol. 47 (6): 1189–96. PMID 7603459.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ 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)
  11. ^ Hunter, A (2006). "Kava (Piper methysticum) back in circulation". Australian Centre for Complementary Medicine. 25 (7): 529.

External links

  • 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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