Regulation of Neuronal GPCR Signaling

University Of Florida, Gainesville FL

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Abstract

PROJECT SUMMARY G protein Coupled Receptor (GPCR) signal transduction pathways play a pivotal role in the development of substance abuse. Many drugs of abuse including opioids and psychostimulants produce their effects by activating GPCRs expressed in generalized brain reward circuitry. Our long-term goal is to elucidate molecular and cellular mechanisms that govern GPCR signaling and cross-talk as a necessary prerequisite to understanding events that lead to substance dependence and designing strategies for the therapeutic correction. Current research on mechanisms of opioid use disorder focuses heavily on mu-opioid receptors (MOR), primary target of opioid drugs responsible for their clinically significant effects including analgesia and euphoria. However, regulatory mechanisms of MOR and its coordination with other GPCRs in neurons in brain reward circuitry are incompletely understood. Through systematic unbiased genetic screening efforts, we have discovered that MOR's actions are closely coordinated with a poorly studied orphan receptor- GPR139. We have identified an endogenous peptide ligand for GPR139 and found that it triggers distinct signaling reactions to oppose MOR effects on behavior. This sets an unprecedented opportunity to understand mechanisms of GPCR cross-talk in neuronal reward circuit while studying how it affects opioid actions at molecular, cellular, and behavioral levels. Based on accumulated data we hypothesize that GPR139 antagonistically intersects with MOR at multiple levels that include activation of unique set of G proteins, coordinated recruitment of -arrestins and convergence at the downstream effector level by modulating second messenger cAMP and activity of ion channels regulating activity of neurons in key structures involved in reward processing and opioid actions. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to (1) understand molecular mechanisms of GPR139 regulation and its interplay with GPCRs, (2) determine mechanisms of GPR139 actions in regulating neuronal activity and (3) probe behavioral and circuit relevance of GPR139 influence in controlling responses to opioids. The strategy proposed to address these Aims will entail a synergistic combination of genetic, biochemical, and physiological approaches, exploiting a powerful array of reagents, animal models, and innovative assays. We hope that by focusing on GPR139 as a new target, completion of these studies will offer means for altering processing of opioid signals advancing the overall goal to develop therapeutics for opioid use disorder.