- Gamma-aminobutyric acid
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Gamma-aminobutyric acid (GABA) is the chief inhibitory
neurotransmitterin the mammalian central nervous system. It plays an important role in regulating neuronal excitability throughout the nervous system. GABA is also directly responsible for the regulation of muscle tone.
Unlike its function in mammals, GABA acts on excitatory receptors in
Although some GABA can be found in pancreatic islet cells and
kidney, there are no significant amounts of GABA in mammalian tissues other than the tissues of the nervous system.fact|date=June 2008
In spastic cerebral palsy in
humans, GABA cannot be absorbed properly by the damaged nerve rootlets corresponding to affected muscles, which leads to hypertoniain those muscles.
Disrupted GABAergic signaling has been implicated in numerous and varied neurological and psychiatric pathologies including movement and
anxiety disorders, epilepsy, schizophrenia, and addiction.
GABA is technically an
amino acid, though it is rarely referred to as such. This is because the term "amino acid", used without a qualifier, refers to the alpha amino acids. GABA is not an alpha amino acid, nor is it incorporated into proteins.
vertebrates, GABA acts at inhibitory synapses in the brainby binding to specific transmembrane receptors in the plasma membraneof both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chlorideions into the cell or positively charged potassiumions 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
hippocampusand neocortexof 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 exhibits excitatory actions in
insects, mediating muscleactivation 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
neonataland adult stages. That is to say, GABA's role changes from excitatory to inhibitory as the brain develops into adulthood.
tructure 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 chemistrycalculations. 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 solvationeffects. 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. [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] [Anne-Marie Sapse. "Molecular Orbital Calculations for Amino Acids and Peptides". Birkhäuser, 2000. ISBN 0817638938.]
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.cite book | author = Roth, Robert J.; Cooper, Jack R.; Bloom, Floyd E. | title = The Biochemical Basis of Neuropharmacology | publisher = Oxford University Press | location = Oxford [Oxfordshire] | year = 2003 | pages = 416 pages | isbn = 0-19-514008-7 | oclc = | doi = ]
Organisms synthesize GABA from
glutamateusing the enzyme L-glutamic acid decarboxylaseand pyridoxal phosphateas a cofactor. It is worth noting that this process converts the principal excitatory neurotransmitter (glutamate) into the principal inhibitory one (GABA).
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 amnesiaand 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
Drugs that affect GABA receptors:
alcohol( ethanol)cite journal | author = Dzitoyeva S, Dimitrijevic N, Manev H | title = Gamma-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila: adult RNA interference and pharmacological evidence | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 9 | pages = 5485–90 | year = 2003 | pmid = 12692303 | doi = 10.1073/pnas.0830111100 ] cite journal | author = Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA, Harrison NL | title = Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors | journal = Nature | volume = 389 | issue = 6649 | pages = 385–9 | year = 1997 | pmid = 9311780 | doi = 10.1038/38738 ] cite journal | author = Boehm SL, Ponomarev I, Blednov YA, Harris RA | title = From gene to behavior and back again: new perspectives on GABAA receptor subunit selectivity of alcohol actions | journal = Adv. Pharmacol. | volume = 54 | issue = | pages = 171–203 | year = 2006 | pmid = 17175815 | doi = 10.1016/j.bcp.2004.07.023 ]
avermectins— doramectin, selamectin, ivermectin
bicucullines - GABA antagonist
benzodiazepinesDiaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.]
baicalinand baicalein from skullcap scutellaria lateriflora
carbamazepinescite journal | author = Granger P, Biton B, Faure C, Vige X, Depoortere H, Graham D, Langer SZ, Scatton B, Avenet P | title = Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin | journal = Mol. Pharmacol. | volume = 47 | issue = 6 | pages = 1189–96 | year = 1995 | pmid = 7603459 | doi = | issn = | url = http://molpharm.aspetjournals.org/cgi/content/abstract/47/6/1189]
cyclopyrrolonederivatives such as zopiclone
gamma-Hydroxybutyric acid(GHB)cite journal | author = Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H | title = Drosophila GABAB receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB) | journal = Eur. J. Pharmacol. | volume = 519 | issue = 3 | pages = 246–52 | year = 2005 | pmid = 16129424 | doi = 10.1016/j.ejphar.2005.07.016 ]
imidazopyridinederivatives such as zolpidem
kavalactonescite journal | author=Hunter, A | title=Kava (Piper methysticum) back in circulation | journal=Australian Centre for Complementary Medicine | volume=25 | issue=7 | year=2006 | pages=529]
pyrazolopyrimidinederivatives such as zaleplon
* Valerian extract
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
Spastic diplegia, a GABA deficiency neuromuscular neuropathology
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