The Ghrelin Receptor (GHSR1a), But Not Ghrelin, Is Essential for Dopamine Receptor-2 (DRD2) Agonist-Induced Anorexia

Abstract

It appears paradoxical that ghrelin receptor (GHSR1a) is expressed in areas of the brain where ghrelin is not produced and where exposure to endogenous ghrelin is unlikely. We show that GHSR1a serves important functional roles in the absence of ghrelin. Non-ghrelin occupied GHSR1a (apo-GHSR1a) modifies canonical dopamine signaling through dopamine receptor-2 (DRD2) by formation of GHSR1a:DRD2 heteromers in native brain tissue. Apo-GHSR1a, but not ghrelin, is essential for the anorexigenic of a DRD2 agonist. These findings illustrate that in neurons expressing both GHSR1a and DRD2, GHSR1a allosterically modifies dopamine signaling and dopamine function. Most importantly, a GHSR1a selective antagonist blocks dopamine signaling in neurons containing both DRD2 and GHSR1a. The therapeutic implications of these results are profound, because by designing agents to selectively target GHSR1a:D2R or GHSR1a:D1R dimers, pharmacological manipulation of dopamine signaling can be targeted to subsets of neurons that co-express GHSR1a and DRD2 without affecting signaling in neurons expressing DRD2 alone. This approach of selective fine-tuning of dopamine signaling provides exciting opportunities for designing next generation therapeutics for feeding disorders and psychiatric disorders associated with abnormal dopamine signaling.