GABA receptor

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[edit] The GABA Receptors

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 (Kuffler and Edwards, 1958, Kravitz, 1963, Krnjevic and Schwartz, 1967, Takeuchi and Takeuchi, 1967, Takeuchi and Takeuchi, 1969). This channel was subsequently termed GABAA receptor (Takeuchi and Onodera, 1972). Fast responding GABA receptors are members of family of Cys-loop ligand-gated ion channels (for review see Barnard et al., 1998, Hevers and Luddens, 1998, Sieghart and Sperk, 2002). Members of this superfamily possess a characteristic loop formed by a disulphide bond between two cysteine residues. They include nicotinic acetylcholine receptors, GABAA and GABAС receptors, glycine and 5-HT3 receptors.


A second type of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABAA receptor channels such as benzodiazepines and barbiturates (Sivilotti and Nistri, 1991, Bormann and Feigenspan, 1995, Johnston, 1996)., was designated GABAС receptor (Drew et al., 1984) (for review see Zhang et al., 2001). Native responses of the GABAС receptor type occur in retinal bipolar or horizontal cells across vertebrate species (Feigenspan et al., 1993, Quian and Dowling, 1993, Lukasiewicz, 1996, Wegelius, 1998). GABAС receptors are exclusively composed of r subunits that are related to GABAA receptor subunits (Shimada et al., 1992, Kusama et al., 1993a, b). Although the term “GABAС receptors” is still being used frequently they are re-assigned as part of GABAA receptor family (Barnard et al., 1998). In ionotropic GABAA and GABAС receptors binding of GABA molecules to their binding sites in the extracellular part of receptor triggers opening of an intrinsic chloride-selective pore. Opening of a chloride conductance drives the membrane potential towards the reversal potential of the Cl¯ ion which is about –80 mV in neurons. As a consequence, firing of new action potentials is inhibited. However, there are numerous reports on GABAA receptors, which are act excitatory. This phenomenon is due to increased intracellular concentration of Cl– ions either during development of the nervous system (Ben-Ari et al., 1997, Taketo and Yoshioka, 2000) or in certain cell populations (Tomiko et al., 1983, Cherubini et al., 1991, Lamsa and Taira, 2003).


A slow response to GABA is mediated by GABAB receptors (for review see Bowery et al., 2002) originally defined on the basis of pharmacological properties (Bowery et al., 1980). 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 (Bein, 1972, Keberle and Faigle, 1972) 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 (Hill and Bowery, 1981). cDNA cloning confirmed that the GABAB receptor belongs to the family of G-protein coupled receptors (Kaupmann et al., 1997). Additional information on GABAB receptors has been reviewed elsewhere (e.g. Enna, 1997, Enna and Bowery, 1997, Kaupmann et al., 1998a,b, Marshall et al., 1999a, Marshall et al., 1999b, Bowery and Enna, 2000, Enna, 2000).

Thus, GABAA and GABAС receptors are ligand-gated ion channels, whereas GABAB receptors are coupled to G proteins. This has a parallel to nicotinic and muscarinic acetylcholine receptors, to [[5-HT3 and metabotropic serotonin receptors, to ionotropic and metabotropic glutamate receptors, or to ionotropic nucleotide-gated P2X and G protein-coupled P2Y receptors.


[edit] See also

[edit] References

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