Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Dysfunctions in GABA-mediated inhibition have been implicated in the etiology of several brain disorders (e.g. epilepsy and anxiety) and GABA receptors are the target for a variety of neuroactive compounds including barbiturates, benzodiazepines, and neurosteroids. In addition to being modulated by these external ligands, GABA receptors are regulated by protein kinase signaling cascades. This regulation can entail an alteration of functional properties of the receptor and/or dynamic control of cell surface expression; the latter of which most certainly involves interactions of the receptors with the cytoskeletal network. It is now evident that the specificity and efficiency of kinase regulation is controlled by a compartmentalization of the kinase and substrate. This compartmentalization allows local changes in intracellular second messengers (for example cAMP or Ca2+) to lead to a phosphorylation of the receptor, and perhaps other associated proteins, thereby locally regulating ion channel function and expression. While it is known that GABA receptors are regulated by kinases, this emergent view on the spatial relationship between kinase and receptor has not been demonstrated. In this application, evidence is provided for a direct association of GABA receptors with signaling cascades and cytoskeletal elements. Building on these preliminary observations, this proposal will investigate the ramifications of the convergence of the PKA and PKC signaling pathways on GABA receptor function. In addition, experiments are proposed that will further elucidate the spatial associations between GABA receptors, kinases, and the cytoskeletal network, as this will certainly be a crucial factor in the regulation of synaptic inhibition in the CNS.
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