GABA receptor

Gamma-aminobutyric acid

The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. GABA receptors influence cognition by coordinating with glutamatergic processes.[1] There are two classes of GABA receptors: GABAA and GABAB.

GABAA receptors are ligand-gated ion channels (also known as ionotropic receptors); whereas GABAB receptors are G protein-coupled receptors, also called metabotropic receptors.

Ligand-gated ion channels: GABAA

Cell GABA receptor.

It has long been recognized that the fast response of neurons to GABA that is blocked by bicuculline and picrotoxin is due to direct activation of an anion channel.[2][3][4][5][6] This channel was subsequently termed the GABAA receptor.[7] Fast-responding GABA receptors are members of a family of Cys-loop ligand-gated ion channels.[8][9][10] Members of this superfamily, which includes nicotinic acetylcholine receptors, GABAA receptors, glycine and 5-HT3 receptors, possess a characteristic loop formed by a disulfide bond between two cysteine residues.

In ionotropic GABAA receptors, binding of GABA molecules to their binding sites in the extracellular part of the receptor triggers opening of a chloride ion-selective pore. The increased chloride conductance drives the membrane potential towards the reversal potential of the Cl¯ ion which is about –65 mV in neurons, inhibiting the firing of new action potentials. This mechanism is responsible for the sedative effects of GABAA allosteric agonists. In addition, activation of GABA receptors lead to the so-called [shunting inhibition], which reduces the excitability of the cell independent of the changes in membrane potential.

There have been numerous reports of excitatory GABAA receptors. According to the excitatory GABA theory, this phenomenon is due to increased intracellular concentration of Cl¯ ions either during development of the nervous system[11][12] or in certain cell populations.[13][14][15] After this period of development, a chloride pump is upregulated and inserted into the cell membrane, pumping Cl− ions into the extracellular space of the tissue. Further openings via GABA binding to the receptor then produce inhibitory responses. Over-excitation of this receptor induces receptor remodeling and the eventual invagination of the GABA receptor. As a result, further GABA binding becomes inhibited and inhibitory postsynaptic potentials are no longer relevant.

However, the excitatory GABA theory has been questioned as potentially being an artefact of experimental conditions, with most data acquired in in-vitro brain slice experiments susceptible to un-physiological milieu such as deficient energy metabolism and neuronal damage. The controversy arose when a number of studies have shown that GABA in neonatal brain slices becomes inhibitory if glucose in perfusate is supplemented with ketone bodies, pyruvate, or lactate,[16][17] or that the excitatory GABA was an artefact of neuronal damage.[18] Subsequent studies from originators and proponents of the excitatory GABA theory have questioned these results,[19][20][21] but the truth remained elusive until the real effects of GABA could be reliably elucidated in intact living brain. Since then, using technology such as in-vivo electrophysiology/imaging and optogenetics, two in-vivo studies have reported the effect of GABA on neonatal brain, and both have shown that GABA is indeed overall inhibitory, with its activation in the developing rodent brain not resulting in network activation,[22] and instead leading to a decrease of activity.[23][24]

GABAA-ρ subclass (formerly GABAC)

Main article: GABAA-rho receptor

A subclass of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABAA receptor channels such as benzodiazepines and barbiturates,[25][26][27] was designated GABAС receptor.[28][29] Native responses of the GABAC receptor type occur in retinal bipolar or horizontal cells across vertebrate species.[30][31][32][33]

GABAС receptors are exclusively composed of ρ (rho) subunits that are related to GABAA receptor subunits.[34][35][36] Although the term "GABAС receptor" is frequently used, GABAС may be viewed as a variant within the GABAA receptor family.[8] Others have argued that the differences between GABAС and GABAA receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors.[37][38] However, since GABAС receptors are closely related in sequence, structure, and function to GABAA receptors and since other GABAA receptors besides those containing ρ subunits appear to exhibit GABAС pharmacology, the Nomenclature Committee of the IUPHAR has recommended that the GABAС term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABAA receptors (GABAA-ρ).[39]

G protein coupled receptor: GABAB

Main article: GABAB receptor

A slow response to GABA is mediated by GABAB receptors,[40] originally defined on the basis of pharmacological properties.[41]

In studies focused on the control of neurotransmitter release, it was noted that a GABA receptor was responsible for modulating evoked release in a variety of isolated tissue preparations. This ability of GABA to inhibit neurotransmitter release from these preparations was not blocked by bicuculline, was not mimicked by isoguvacine, and was not dependent on Cl¯, all of which are characteristic of the GABAA receptor. The most striking discovery was the finding that baclofen (β-parachlorophenyl GABA), a clinically employed spasmolytic[42][43] mimicked, in a stereoselective manner, the effect of GABA.

Later ligand-binding studies provided direct evidence of binding sites for baclofen on central neuronal membranes.[44] cDNA cloning confirmed that the GABAB receptor belongs to the family of G-protein coupled receptors.[45] Additional information on GABAB receptors has been reviewed elsewhere.[46][47][48][49][50][51][52][53]

See also

References

  1. ↑ Farahmandfar, Maryam; Akbarabadi, Ardeshir; Bakhtazad, Atefeh; Zarrindast, Mohammad-Reza (2016-03-01). "Recovery from ketamine-induced amnesia by blockade of GABA-A receptor in medial prefrontal cortex of mice". Neuroscience. doi:10.1016/j.neuroscience.2016.02.056. ISSN 1873-7544. PMID 26944606.
  2. ↑ Kuffler SW, Edwards C (November 1958). "Mechanism of gamma aminobutyric acid (GABA) action and its relation to synaptic inhibition". J. Neurophysiol. 21 (6): 589–610. PMID 13599049.
  3. ↑ Kravitz EA, Kuffler SW, Potter DD (September 1963). "Gamma-aminobutyric acid and other blocking compounds in crustacea. III. Their relative concentrations in separated motor and inhibitory axons". J. Neurophysiol. 26: 739–51. PMID 14065325.
  4. ↑ Krnjević K, Schwartz S (1967). "The action of gamma-aminobutyric acid on cortical neurones". Exp Brain Res. 3 (4): 320–36. doi:10.1007/BF00237558. PMID 6031164.
  5. ↑ Takeuchi A, Takeuchi N (August 1967). "Anion permeability of the inhibitory post-synaptic membrane of the crayfish neuromuscular junction". J. Physiol. (Lond.). 191 (3): 575–90. doi:10.1113/jphysiol.1967.sp008269. PMC 1365493Freely accessible. PMID 6051794.
  6. ↑ Takeuchi A, Takeuchi N (November 1969). "A study of the action of picrotoxin on the inhibitory neuromuscular junction of the crayfish". J. Physiol. (Lond.). 205 (2): 377–91. doi:10.1113/jphysiol.1969.sp008972. PMC 1348609Freely accessible. PMID 5357245.
  7. ↑ Takeuchi A, Onodera K (March 1972). "Effect of bicuculline on the GABA receptor of the crayfish neuromuscular junction". Nature New Biol. 236 (63): 55–6. doi:10.1038/236055a0. PMID 4502428.
  8. 1 2 Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (June 1998). "International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function". Pharmacol. Rev. 50 (2): 291–313. PMID 9647870.
  9. ↑ Hevers W, Lüddens H (August 1998). "The diversity of GABAA receptors. Pharmapoo and electrophysiological properties of GABAA channel subtypes". Mol. Neurobiol. 18 (1): 35–86. doi:10.1007/BF02741459. PMID 9824848.
  10. ↑ Sieghart W, Sperk G (August 2002). "Subunit composition, distribution and function of GABA(A) receptor subtypes". Curr Top Med Chem. 2 (8): 795–816. doi:10.2174/1568026023393507. PMID 12171572.
  11. ↑ Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL (November 1997). "GABAA, NMDA and AMPA receptors: a developmentally regulated 'ménage à trois'". Trends Neurosci. 20 (11): 523–9. doi:10.1016/S0166-2236(97)01147-8. PMID 9364667.
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  16. ↑ Rheims, Sylvain; Holmgren, Carl D.; Chazal, Genevieve; Mulder, Jan; Harkany, Tibor; Zilberter, Tanya; Zilberter, Yuri (August 2009). "GABA action in immature neocortical neurons directly depends on the availability of ketone bodies". Journal of Neurochemistry. 110 (4): 1330–1338. doi:10.1111/j.1471-4159.2009.06230.x.
  17. ↑ Holmgren, Carl D.; Mukhtarov, Marat; Malkov, Anton E.; Popova, Irina Y.; Bregestovski, Piotr; Zilberter, Yuri (February 2010). "Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity in the neonatal cortex". Journal of Neurochemistry. 112 (4): 900–912. doi:10.1111/j.1471-4159.2009.06506.x.
  18. ↑ Dzhala, V.; Valeeva, G.; Glykys, J.; Khazipov, R.; Staley, K. (21 March 2012). "Traumatic Alterations in GABA Signaling Disrupt Hippocampal Network Activity in the Developing Brain". Journal of Neuroscience. 32 (12): 4017–4031. doi:10.1523/JNEUROSCI.5139-11.2012.
  19. ↑ Kirmse, K.; Witte, O. W.; Holthoff, K. (24 November 2010). "GABA Depolarizes Immature Neocortical Neurons in the Presence of the Ketone Body -Hydroxybutyrate". Journal of Neuroscience. 30 (47): 16002–16007. doi:10.1523/JNEUROSCI.2534-10.2010.
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