GABAA receptors (GABAR) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system (CNS), and are thus critical to normal and disease CNS function. There are a family of similar but distinct GABAR subtypes which vary in pharmacological and biological properties. In addition GABAR are located in different parts of the neuronal cell membrane and in synaptic cultures as well as non- synaptic membrane. The trafficking, targeting, clustering, and turnover of synaptic receptors in just beginning to be studied. In particular, cellular proteins that interact with the intracellular domains of GABAR may serve to anchor and cluster receptors at synapses at synapses, as well as to establish and reconstruct synapses and their receptors during plasticity events. We will study the function of several cellular proteins that interact with GABAR that we identified using the yeast two-hybrid system. GABARAP (GABA Receptor Associated Protein) links GABAR gamma2 subunit to microtubules and clusters GABAR at synapses. RACK1 (receptor for activated C-kinase), links protein kinase C-beta to GABAR alpha1 subunit, probably for regulating some aspect of GABAR function by protein phosphorylation with PKC. Studies on these and related proteins will allow us to take a close look a dynamic and important cellular biology of these important brain neurotransmitter receptors.
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