GABA receptor

GABA receptor

The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the mature vertebrate central nervous system. 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 known as metabotropic receptors).

Contents

  • Ligand-gated ion channels: GABAA 1
    • GABAA-ρ subclass (formerly GABAC) 1.1
  • G protein coupled receptor: GABAB 2
  • Other receptors 3
  • See also 4
  • References 5
  • External links 6

Ligand-gated ion channels: GABAA

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.[1][2][3][4][5] This channel was subsequently termed the GABAA receptor.[6] Fast-responding GABA receptors are members of family of Cys-loop ligand-gated ion channels.[7][8][9] 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.

However, there are numerous reports of excitatory GABAA receptors. This phenomenon is due to increased intracellular concentration of Cl¯ ions either during development of the nervous system[10][11] or in certain cell populations.[12][13][14]

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 IPSPs are no longer relevant.

GABAA-ρ subclass (formerly GABAC)

A subclass of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABAA receptor channels such as benzodiazepines and barbiturates,[15][16][17] was designated GABAС receptor.[18][19] Native responses of the GABAC receptor type occur in retinal bipolar or horizontal cells across vertebrate species.[20][21][22][23]

GABAС receptors are exclusively composed of ρ (rho) subunits that are related to GABAA receptor subunits.[24][25][26] Although the term "GABAС receptor" is frequently used, GABAС may be viewed as a variant within the GABAA receptor family.[7] 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.[27][28] 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).[29]

G protein coupled receptor: GABAB

A slow response to GABA is mediated by GABAB receptors,[30] originally defined on the basis of pharmacological properties.[31]

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[32][33] 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.[34] cDNA cloning confirmed that the GABAB receptor belongs to the family of G-protein coupled receptors.[35] Additional information on GABAB receptors has been reviewed elsewhere.[36][37][38][39][40][41][42][43]

Other receptors

This has a parallel to several other receptors in the body, in which a single molecule binds to receptors which function in completely different ways:

See also

References

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  2. ^ 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.  
  3. ^ Krnjević K, Schwartz S (1967). "The action of gamma-aminobutyric acid on cortical neurones". Exp Brain Res 3 (4): 320–36.  
  4. ^ 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.  
  5. ^ 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.  
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  9. ^ Sieghart W, Sperk G (August 2002). "Subunit composition, distribution and function of GABA(A) receptor subtypes". Curr Top Med Chem 2 (8): 795–816.  
  10. ^ 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.  
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  19. ^ Zhang D, Pan ZH, Awobuluyi M, Lipton SA (March 2001). "Structure and function of GABA(C) receptors: a comparison of native versus recombinant receptors". Trends Pharmacol. Sci. 22 (3): 121–32.  
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  21. ^ Qian H, Dowling JE (January 1993). "Novel GABA responses from rod-driven retinal horizontal cells". Nature 361 (6408): 162–4.  
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  35. ^ Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H, Froestl W, Bettler B (March 1997). "Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors". Nature 386 (6622): 239–46.  
  36. ^ Enna SJ (October 1997). "GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities". Expert Opin Investig Drugs 6 (10): 1319–25.  
  37. ^ Bowery, N. G.; Enna, S. J. (1997). The GABA receptors. Totowa, NJ: Humana Press.  
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External links

  • receptorsBIUPHAR GPCR Database - GABA
  • GABA Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)