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Novel striatum orphan G protein-coupled receptors regulate dopamine D2 receptors by controlling cAMP

Katherine Ferry

University of Texas Medical Branch

The striatum performs essential brain functions including movement control, regulation of attention, and is a critical component of the reward system. Deficient striatal function is the pathophysiological underpinning of a variety of neuropsychiatric disorders including schizophrenia, depression, and addiction. Current FDA approved drugs targeting these diseases have displayed limited clinical effectiveness, with many eliciting severe adverse events. Thus, new druggable targets are necessary to improve treatment for these debilitating diseases. Of the 350 non-sensory G protein-coupled receptors (GPCRs), nearly 120 remain orphan receptors, whose endogenous ligands and G protein signaling are unknown. Using comparative transcriptome profiling and the Genotype Tissue Expression (GTEx) database, our lab has identified 7 orphan GPCRs specifically expressed in the human striatum. The novel striatum receptors include GPR6, GPR52, GPR55, GPR88, GPR101, GPR139, and GPR149, which are all class A orphan GPCRs. When these receptors were expressed in HEK293 cells, GPR6, GPR52, and GPR101 profoundly increased cAMP levels, suggesting activation of the Gs/adenylyl cyclase pathway, while GPR88 basally decreased cAMP levels, indicating Gi/o inhibition of adenylyl cyclase. Because several of these novel receptors are expressed in dopamine D2 receptors (D2R) containing striatal neurons in the brain, we hypothesized that GPR6, GPR52, and GPR101 may cross-talk with D2R signaling by modulating cAMP levels. To test this hypothesis, we co-transfected GPR6, GPR52, or GPR101 with the D2R in HEK293 cells and assessed basal as well as D2R agonist-induced changes in cAMP levels. Strikingly, co-transfection of GPR52, GPR6, or GPR101 elevated basal cAMP which increased the efficacy of the D2R agonist quinpirole to inhibit adenylyl cyclase activity. This suggests that GPR6, GPR52, and GPR101 exhibits signaling crosstalk with D2 dopamine receptors and these novel orphan receptors set the basal tone of cAMP in cells. Taken together, we have discovered several striatum selective receptors signal via the Gs/adenylyl cyclase/cAMP pathway allowing signaling crosstalk with the classic D2 dopamine receptor. Our findings also suggest GPR6, GPR52, and GPR101 are potential drug targets to potentially modulate dopamine pathways involved in neuropsychiatric diseases. These findings also pave the way for novel neurobiology mechanisms and drug targets for treating neuropsychiatric disorders.

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