Timely initiation and cessation of intercellular communication via heterotrimeric G protein-coupled receptors (GPCRs) is crucial for normal functioning of brain and sensory neurons. Aberration of this process can lead to pathophysiological deficits in peripheral or central nervous system activity;conversely, stimulation, prolongation, or antagonism of GPCR signaling underlies the actions of many psychoactive and neurotropic agents. In 1996, a new class of proteins was discovered that directly modulate the timing of GPCR signaling - the """"""""regulators of G-protein signaling"""""""" (RGS) proteins. The overall goal of the Siderovski laboratory is to identify specific roles for RGS proteins in (patho)physiological process and thus establish select members of the RGSfamily as viable drug discovery targets. RGS12 is specifically involved in determining desensitization from GABA(B) receptor-mediated inhibition of presynaptic calcium current in dorsal root ganglia. Our long-term objective is to define the molecular determinants that constitute the desensitization function of RGS12. Beyond the hallmark GTPase-accelerating activity specified by the RGS12 RGS domain, we have now identified phospholipid- and phosphotyrosine-binding activity within RGS12, as well as its ability to interact with multiple components of the mitogen-activated protein kinase (MAPK) cascade. This proposal therefore describes biochemical/biophysical and cell-biological analyses of RGS12-mediated protein/protein and protein/lipid interactions, coupled with celullar studies of agonist-promoted MAPK signal transduction and electrophysiological assessment of neurotransmitter modulation of Cav2.2 channel activity in the presence of selective RGS12 mutants. Results from this work will help define the specific roles RGS12 partakes in signal transduction and ion channel modulation, as well as illuminate the potential for RGS12 as a drug discovery target for novel therapies for neuropathic pain and spasticity. Many drugs act by binding a particular protein receptor on the cell's surface: a G-protein coupled receptor. Our group discovered a new protein family - the RGS proteins - that interfere with these receptors. We wish to study one RGS protein, RGS12, that interferes with the actions of the neurotransmitter GABA in neurons that control pain processing. This work should lead to the discovery of new pain-controlling drugs.
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