Gamma-Aminobutyric acid: Wikis

  

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gamma-Aminobutyric acid
Gamma-Aminobuttersäure - gamma-aminobutyric acid.svg
GABA3d.png
IUPAC name
Identifiers
CAS number 56-12-2 Yes check.svgY
PubChem 119
MeSH gamma-Aminobutyric+Acid
SMILES
ChemSpider ID 116
Properties
Molecular formula C4H9NO2
Molar mass 103.12 g/mol
Melting point

203.7 °C, 477 K, 399 °F

 Yes check.svgY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

γ-Aminobutyric acid (GABA) (IPA: [ˈgæmə əˈmiːnoʊbjuːˈtɪrɨk ˈæsɨd]) is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a 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.

Although chemically it is a 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 impaired, which leads to hypertonia of the muscles signaled by those nerves.

Contents

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 in which the receptor is part of a ligand-gated ion channel complex, 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. In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.[2]

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 cell's membrane less negative), shunting (has no effect on the cell's membrane) 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 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 of any coincident synaptic input essentially by reducing the electrical resistance of the cell's membrane (essentially equivalent to Ohm's 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.[3]

Development

GABA-producing GAD67 enzyme in the brain slice at 1st postnatal day, with the highest expression in subventricular zone (svz). From Popp et al., 2009.[4]

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.[3]

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.[5][6]

GABA regulates the proliferation of neural progenitor cells[7][8] the migration[9] and differentiation[10][11] the elongation of neurites[12] and the formation of synapses.[13]

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.[14] GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.[15]

Beyond the nervous system

GABAergic mechanisms have been demonstrated in various peripheral tissues and organs including, but not restricted to the intestine, stomach, pancreas, Fallopian tube, uterus, ovary, testis, kidney, urinary bladder, lung and liver.[16]

In 2007, an excitatory GABAergic system was described in the airway epithelium. The system activates following exposure to allergens and may participate in the mechanisms of asthma.[17] GABAergic systems have also been found in the testis[18] and in the eye lens.[19]

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.[20][21]

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.[22]

Synthesis

Organisms synthesize GABA from glutamate using the enzyme L-glutamic acid decarboxylase and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor. This process converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter (GABA).[23][24]

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.[25] 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.

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. doi:10.1016/S0074-7696(02)13011-7. PMID 11837891.  
  2. ^ 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): 233–5. doi:10.1126/science.1121325. PMID 16410524.  
  3. ^ a b Li K, Xu E (June 2008). "The role and the mechanism of gamma-aminobutyric acid during central nervous system development". Neurosci Bull 24 (3): 195–200. doi:10.1007/s12264-008-0109-3. PMID 18500393.  
  4. ^ Popp A, Urbach A, Witte OW, Frahm C (2009). "Adult and embryonic GAD transcripts are spatiotemporally regulated during postnatal development in the rat brain". PLoS ONE 4 (2): e4371. doi:10.1371/journal.pone.0004371. PMID 19190758. PMC 2629816. http://dx.plos.org/10.1371/journal.pone.0004371.  
  5. ^ 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.  
  6. ^ Jelitai M, Madarasz E (2005). "The role of GABA in the early neuronal development" (). Int. Rev. Neurobiol. 71: 27–62. doi:10.1016/S0074-7742(05)71002-3. PMID 16512345. http://www.iem.cas.cz/Data/files/pdf/neuroscience/2004/jelitai-2004.pdf.  
  7. ^ 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): 1287–98. doi:10.1016/0896-6273(95)90008-X. PMID 8845153.  
  8. ^ 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. PMID 10908617. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=10908617.  
  9. ^ 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. PMID 9698329. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=9698329.  
  10. ^ 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): 150–4. doi:10.1016/0304-3940(93)90505-F. PMID 8390627.  
  11. ^ 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.  
  12. ^ 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. PMID 11264309. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11264309.  
  13. ^ Ben-Ari Y (September 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.  
  14. ^ 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. PMID 12163549. http://jn.physiology.org/cgi/pmidlookup?view=long&pmid=12163549.  
  15. ^ 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. PMID 18852839.  
  16. ^ Erdö SL, Wolff JR (1990). "gamma-Aminobutyric acid outside the mammalian brain". J. Neurochem. 54 (2): 363–72. doi:10.1111/j.1471-4159.1990.tb01882.x. PMID 2405103.  
  17. ^ Xiang, Y.; Wang, S.; Liu, M.; Hirota, J.; Li, J.; Ju, W.; Fan, Y.; Kelly, M. et al. (2007). "A GABAergic system in airway epithelium is essential for mucus overproduction in asthma". Nature medicine 13 (7): 862–867. doi:10.1038/nm1604. PMID 17589520.   edit
  18. ^ Payne, Anita H.; Matthew H. Hardy (2007). The Leydig cell in health and disease. Humana Press. ISBN 1588297543, ISBN 9781588297549.  
  19. ^ Kwakowsky, A.; Schwirtlich, M.; Zhang, Q.; Eisenstat, D.; Erdélyi, F.; Baranyi, M.; Katarova, Z.; Szabó, G. (2007). "GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: correlation with Dlx2 and Dlx5". Developmental dynamics : an official publication of the American Association of Anatomists 236 (12): 3532–3544. doi:10.1002/dvdy.21361. PMID 17969168.   edit
  20. ^ Devashis Majumdar and Sephali Guha.(1988). "Conformation, electrostatic potential and pharmacophoric pattern of GABA (gamma-aminobutyric acid) and several GABA inhibitors." Journal of Molecular Structure: THEOCHEM 180: 125-140. doi:10.1016/0166-1280(88)80084-8
  21. ^ Anne-Marie Sapse. Molecular Orbital Calculations for Amino Acids and Peptides. Birkhäuser, 2000. ISBN 0817638938.
  22. ^ 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.  
  23. ^ Petroff OA (December 2002). "GABA and glutamate in the human brain". Neuroscientist 8 (6): 562–73. doi:10.1177/1073858402238515. PMID 12467378. http://nro.sagepub.com/cgi/pmidlookup?view=long&pmid=12467378.  
  24. ^ 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.  
  25. ^ 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.  
  26. ^ 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.  
  27. ^ 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.  
  28. ^ 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: 171–203. doi:10.1016/j.bcp.2004.07.023. PMID 17175815.  
  29. ^ 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.  

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. http://www.vcu-cme.org/gaba/overview.html. Retrieved 2008-06-20. "The role of GABA in the pathogenesis and treatment of anxiety and other neuropsychiatric disorders"  
  • Scholarpedia article on GABA

Simple English

Gamma-Aminobutyric acid (γ-Aminobutyric acid, GABA) (IPA: [ˈgæmə əˈmiːnoʊbjuːˈtɪrɨk ˈæsɨd]) is a neurotransmitter in the central nervous system of mammals. It is an inhibiting neurotransmitter. Normally, when a neuron receives an impulse, it will make the signal stronger. In the case where there is an inhibiting neurotransmitter, the cell will no longer get the impulse, and the signal as a whole will be weakened.

In mammals, GABA regulates how much neurons in the central nervous system will be stimulated. In humans, GABA is also inhibitory neurotransmitter in the mammalian central nervous system. It plays a 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.

Even though chemically it is an amino acid, GABA is rarely referred to as such in the scientific or medical communities. The term "amino acid," used without a qualifier, refers to the alpha amino acids, which GABA is not. GABA is also not incorporated into proteins.

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

References

  1. Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H (2002). [Expression error: Unexpected < operator "GABA and GABA receptors in the central nervous system and other organs"]. Int. Rev. Cytol. 213: 1–47. doi:10.1016/S0074-7696(02)13011-7. PMID 11837891. 








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