Orphan Receptors in Regulation of Neuronal G Protein Signaling

About This Grant

PROJECT SUMMARY G protein coupled receptor (GPCR) signaling pathways mediate actions of hormones and neurotransmitters. They are essential for the normal function of the nervous system, frequently disrupted in many neuropsychiatric and neurological conditions and/or exploited for therapeutic purposes. While we learned considerable information about molecular players involved in traditional GPCR signaling, many critical gaps remain. Among the biggest uncharted territories in the field is an issue of “orphan” GPCRs, receptors with unknown signaling mechanisms. It is generally recognized that orphan receptors have tremendous potential for uncovering novel biology of the nervous system and harnessing it for potential therapeutic benefits. Our long- term goal is to understand principles in organization and functional regulation of poorly explored GPCR pathways in the effort to develop better treatments for brain disorders. The focus of our attention is on the poorly understood orphan receptor- GPR158, that plays a pivotal role in stress-induced depression. During the previous award period we demonstrated that GPR158 serves as a receptor for major neurotransmitter glycine impacting synaptic transmission and neuronal excitability. We further delineated GPR158 signaling mechanism showing that it associates with a negative regulator of G protein signaling, RGS7 as well as extracellular synaptic proteins and controls production of the second messenger cAMP. We further solved a structure of GPR158 in complex with RGS7 revealing its organization at atomic level. These data led to an overarching hypothesis that glycine signals via GPR158 regulate activity of the associated RGS7 complex which in turn gates cAMP production to regulate neuronal activity that drives stress- induced behavioral changes. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to: (1) establish molecular mechanisms of glycine action on GPR158, (2) delineate structural basis of glycine effects on GPR158 and interaction with binding partners and (3) dissect mechanics of GPR158 signal transduction in regulation of cAMP. The strategy proposed to address these Aims will entail a synergistic combination of biochemical, structural, and cell-biological approaches, exploiting the existence of a powerful array of technologies and animal models. We hope that accomplishment of these goals will provide critical new insights into the mood regulation in mammals and suggest novel targets for the development of therapeutic interventions.