gamma-Aminobutyric acid

"GABA" redirects here. For other uses, see GABA (disambiguation).
gamma-Aminobutyric acid
GABA molecule
Names
IUPAC name
4-aminobutanoic acid
Identifiers
56-12-2 YesY
ChEBI CHEBI:16865 N
ChEMBL ChEMBL96 YesY
ChemSpider 116 YesY
DrugBank DB02530 YesY
EC Number 200-258-6
1067
Jmol interactive 3D Image
KEGG D00058 YesY
MeSH gamma-Aminobutyric+Acid
PubChem 119
RTECS number ES6300000
UNII 2ACZ6IPC6I YesY
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) 4.23 (carboxyl), 10.43 (amino)[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 YesYN ?)
Infobox references

Gamma-Aminobutyric acid(γ-Aminobutyric acid) /ˈɡæmə əˈmiːnoʊbjuːˈtɪrᵻk ˈæsᵻd/ (also called GABA /ˈɡæbə/ for short) is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays the principal role in reducing neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.[2]

Although in chemical terms it is 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, by convention refers to the alpha amino acids, which GABA is not, nor is it considered to be incorporated into proteins.

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).

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 CNS 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.[3] In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.[4]

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 excitatory/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 excitatory or depolarizing; 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. A developmental switch in the molecular machinery controlling 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 .[5]

Brain development

While GABA is an inhibitory transmitter in the mature brain, its actions are primarily excitatory in the developing brain.[5][6] The gradient of chloride is reversed in immature neurons, and its reversal potential is 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, i.e. a depolarizing current. The differential gradient of chloride in immature neurons is primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABA itself is partially responsible for orchestrating the maturation of ion pumps.[7] GABA-ergic interneurons mature faster in the hippocampus and the GABA signalling machinery appears earlier than glutamatergic transmission. Thus, GABA is the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamatergic synapses.

However, this theory has been questioned based on results showing that in brain slices of immature mice incubated in artificial cerebrospinal fluid (ACSF) (modified in a way that takes into account the normal composition of the neuronal milieu in sucklings by adding an energy substrate alternative to glucose, beta-hydroxybutyrate) GABA action shifts from excitatory to inhibitory mode.[8]

This effect has been later repeated when other energy substrates, pyruvate and lactate, supplemented glucose in the slices' media.[9] Later investigations of pyruvate[10] and lactate[11] metabolism found that the original results were not due to energy source issues but to changes in pH resulting from the substrates acting as "weak acids". These arguments were later rebutted by further findings[12][13] showing that changes in pH even greater than that caused by energy substrates do not affect the GABA-shift described in the presence of energy substrate-fortified ACSF and that the mode of action of beta-hydroxybutyrate, pyruvate and lactate (assessed by measurement NAD(P)H and oxygen utilization) was energy metabolism-related.[14]

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.[15][16] The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.[17]

GABA regulates the proliferation of neural progenitor cells[18][19] the migration[20] and differentiation[7][21] the elongation of neurites[22] and the formation of synapses.[23]

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.[24] GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.[25]

Beyond the nervous system

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); from Popp et al., 2009[26]

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.[27]

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.[28] GABAergic systems have also been found in the testis[29] and in the eye lens.[30]

Structure and conformation

GABA is found mostly as a zwitterion, that is, with the carboxy 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.[31][32]

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.[33]

Bio-synthesis

Gabaergic neurons which produce GABA

Exogenous GABA does not penetrate the blood–brain barrier;[34] it is synthesized in the brain. It is synthesized from glutamate using the enzyme L-glutamic acid decarboxylase (GAD) 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).[35][36] GABA is converted back to glutamate by a metabolic pathway called the GABA shunt.

Catabolism

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.[37]

Pharmacology

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.[38][39] Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.[40]

In general, GABA does not cross the blood–brain barrier,[34] 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.[41] At least one study suggests that orally administered GABA increases the amount of Human Growth Hormone (HGH).[42] 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.[41] 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. This allows 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.

GABA enhanced the catabolism of serotonin into N-Acetylserotonin (the precursor of melatonin) in rats.[43] It is thus suspected that GABA is involved in the synthesis of melatonin and thus may exert regulatory effects on sleep and reproductive functions.

GABAergic drugs

In plants

GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes.[49] It has also a role in cell signalling in plants.[50][51]

See also

References

  1. ↑ Dawson RMC, Elliot DC, Elliot WH, Jones KM, ed. (1959). Data for Biochemical Research. Oxford: Clarendon Press.
  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. 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. ↑ 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.
  4. ↑ 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.
  5. 1 2 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. PMID 18500393.
  6. ↑ 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.
  7. 1 2 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.
  8. ↑ Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y (August 2009). "GABA action in immature neocortical neurons directly depends on the availability of ketone bodies". J. Neurochem. 110 (4): 1330–8. doi:10.1111/j.1471-4159.2009.06230.x. PMID 19558450.
  9. ↑ Holmgren CD, Mukhtarov M, Malkov AE, Popova IY, Bregestovski P, Zilberter Y (February 2010). "Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity in the neonatal cortex in vitro". J. Neurochem. 112 (4): 900–12. doi:10.1111/j.1471-4159.2009.06506.x. PMID 19943846.
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  12. ↑ Mukhtarov M, Ivanov A, Zilberter Y, Bregestovski P (January 2011). "Inhibition of spontaneous network activity in neonatal hippocampal slices by energy substrates is not correlated with intracellular acidification". J. Neurochem. 116 (2): 316–21. doi:10.1111/j.1471-4159.2010.07111.x. PMID 21083663.
  13. ↑ Ivanov A, Mukhtarov M, Bregestovski P, Zilberter Y (2011). "Lactate Effectively Covers Energy Demands during Neuronal Network Activity in Neonatal Hippocampal Slices". Front Neuroenergetics 3: 2. doi:10.3389/fnene.2011.00002. PMC 3092068. PMID 21602909.
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  17. ↑ 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.
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  34. 1 2 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.
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  41. 1 2 Müller EE, Locatelli V, Cocchi D (April 1999). "Neuroendocrine control of growth hormone secretion". Physiol. Rev. 79 (2): 511–607. PMID 10221989.
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  47. ↑ 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.
  48. ↑ 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.
  49. ↑ 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.
  50. ↑ 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.
  51. ↑ 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.
  52. ↑ Parviz, Mahsa, Vogel, Kara, Gibson, K. Michael, & Pearl, Phillip L. (2014). Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies. Journal of Pediatric Epilepsy, 3(4), 217–227. http://doi.org/10.3233/PEP-14097 | PMID = 25485164 | PMCID = PMC4256671 |
  53. ↑ Pearl, Phillip L., Parviz, Mahsa, Hodgeman, Ryan, Gibson, K. Michael. GABA-transaminase deficiency. In: Reimschisel T(ed.) MedLink Neurology. San Diego, California: MedLink Corporation. http://medlink.com/article/gaba-transaminase_deficiency

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