Molecular Signaling and Agonist Discovery for GPR52

GPR52 is a brain-enriched orphan G protein-coupled receptor and has uniquely been described as a self-activating receptor. GPR52 is a promising therapeutic target for the modulation of striatal neurons, wherein agonism may be beneficial for the treatment of schizophrenia and psychiatric disorders. The work herein describes the investigation of GPR52 signaling mechanisms, molecular determinants for GPR52 activation, and discovery of biased GPR52 agonists. GPR52 was determined to couple to both Gs and Golf to increase cAMP signaling, with constitutive activity driven by Gs. GPR52 is co-expressed with D2 dopamine receptors, and in vitro studies show crosstalk at the level of adenylyl cyclase and cAMP signaling. The constitutive activity of GPR52 allows for more dynamic modulation of cAMP by D2R ligands and additionally sets a threshold for maximal activation of both receptors. Essential molecular interactions for GPR52 constitutive activity and ECL2-mediated self-activation were identified through receptor mutagenesis. These studies also gave insight into the key binding site interactions for GPR52 agonists and their mechanism of action as allosteric modulators of ECL2-mediated self-activation. Iterative drug design led to the identification of a new series of GPR52 agonists with improved potency and efficacy. Several of these compounds demonstrated bias for G protein/cAMP signaling relative to β-arrestin recruitment. Two of these new agonists induced significantly less GPR52 desensitization than the parent compound, providing important tools for studying the effects of GPR52 signaling bias. Together, these results provide a mechanistic understanding of GPR52 signaling pathways and molecular determinants for activation, along with characterization of new agonist tools for studying the therapeutic potential of GPR52.

Name thesis:degree_name

Pharmacology and Toxicology (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2025

Author dc:creator

• Murphy, Ryan Edward 1997-

Advisor dc:contributor.advisor

• Allen, John (joaallen@utmb.edu)

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12838

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12838