GABA Receptors

There are two major types of well-characterized GABA receptors, GABAA and GABAB, and most neurons in the CNS possess at least one of these types. The GABAA receptor is the more prevalent of the two in the mammalian CNS and as a result has been extensively studied and characterized. GABAA contains an integral transmembrane chloride channel, which is opened upon receptor activation, generally resulting in hyperpolarization of the neuron (i.e., suppressing excitability). The GABA receptor is a heteropentameric glycoprotein of approximately 275 kDa composed of a combination of multiple polypeptide subunits. GABAa displays enormous heterogeneity, being composed of a combination of five classes of polypeptide subunits (ce, (5, 7, 5, £), of which there are at least 18 total subtypes. The various receptors display variation in functional pharmacology, hinting at the multiple finely tuned roles that inhibitory neurotransmission plays in brain function.

It is now well established that benzodiazepines (BZDs) function by binding to a potentiator site on the GABAa receptor, increasing the amplitude and duration of inhibitory postsynaptic currents in response to GABA binding. Coexpression of additional >' subunits is believed to be necessary for the potentiation of GABA-mediated responses by BZDs. In addition to BZDs, barbiturates and ethanol are also believed to exert many of their effects by potentiating the opening of the GABAA receptor chloride channel (see Figure 1-8). As noted earlier, GABAA receptors have a widespread distribution in the brain, and the majority of these receptors in the brain are targets of the currently available BZDs. For this reason, there has been considerable interest in determining if the desirable and undesirable effects of BZDs can be differentiated on the basis of the presence of different subunit composition. Much of the work has used gene knockout technology; thus, mutation of the BZD-binding site of the GCi subunit in mice blocks the sedative, anticonvulsive, and amnesic, but not the anxiolytic, effects of diazepam (see Gould et al. 2003; Mohler et al. 2002). In contrast, the 1:1:2 subunit (expressed highly in the cortex and hippocampus) is necessary for diazepam anxiolysis and myorelaxation. Thus, there is now optimism that an iX2~selective ligand will soon provide effective acute treatment of anxiety disorders without the unfavorable side-effect profile of current BZDs. A compound with this preferential affinity has already been demonstrated to exert fewer sedative/depressant effects than diazepam in rat behavioral studies (see Gould et al. 2003; Mohler et al. 2002).

The phosphorylation of GABAA receptors is another mechanism by which this receptor complex can be regulated in function and expression. In this context, it is noteworthy that studies have reported that knockout mice deficient in PKC&. isoforms show reduced anxiety and alcohol consumption and an enhanced response to the effects of BZDs (discussed in Gould et al. 2003). Furthermore, different GABAa receptor subunit partnerships, such as 1x1 ¡5, mediate tonic inhibitory currents in the hippocampus and are highly sensitive to low concentrations of ethanol (Glykys et al. 2007).

The GABAb receptors are coupled to Gi and Go and thereby regulate adenylyl cyclase activity (generally inhibit), K+ channels (open), and Ca2+ channels (close). GABAB receptors can function as an autoreceptor but are also found abundantly postsynaptically on non-GABAergic neurons. Of interest, there is mounting evidence that receptor dimerization may be required for the activation of GABAB and possibly other G protein-coupled receptors; although receptor dimerization has long been known to occur for growth factor and JAK (Janus tyrosine kinase)/STAT (signal transducers and activators of transcription) receptors (discussed later in this chapter), this was not expected for GPCRs. However, studies have reported that coexpression of two GABAb receptor subunits—subunit 1 (GABAbR1) and subunit 2 (GABABR2)—is necessary for the formation of a functional GABAb receptor (Bouvier 2001). Some data suggest that GABABR2 may be necessary for proper protein folding of GABABR1 (acting as a molecular chaperone) in the endoplasmic reticulum, but this remains to be definitively established. Support for the physiological relevance of this dimerization comes from studies showing that the GABAB R1 and R2 subunits can be co-immunoprecipitated in rat cortical membrane preparations (Kaupmann et al. 1997); thus, the dimerization is not simply an in vitro phenomenon.

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