title: Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism.
abstract: We identified subsets of neurons in the brain that coexpress the dopamine receptor subtype-2 (DRD2) and the ghrelin receptor (GHSR1a). Combination of FRET confocal microscopy and Tr-FRET established the presence of GHSR1a:DRD2 heteromers in hypothalamic neurons. To interrogate function, mice were treated with the selective DRD2 agonist cabergoline, which produced anorexia in wild-type and ghrelin⁻/⁻ mice; intriguingly, ghsr⁻/⁻ mice were refractory illustrating dependence on GHSR1a, but not ghrelin. Elucidation of mechanism showed that formation of GHSR1a:DRD2 heteromers allosterically modifies canonical DRD2 dopamine signaling resulting in Gβγ subunit-dependent mobilization of [Ca²⁺](i) independent of GHSR1a basal activity. By targeting the interaction between GHSR1a and DRD2 in wild-type mice with a highly selective GHSR1a antagonist (JMV2959) cabergoline-induced anorexia was blocked. Inhibiting dopamine signaling in subsets of neurons with a GHSR1a antagonist has profound therapeutic implications by providing enhanced selectivity because neurons expressing DRD2 alone would be unaffected.
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute-Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Andras
authors.initials: A
authors.lastname: Kern
authors.forename: Rosie
authors.initials: R
authors.lastname: Albarran-Zeckler
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Walsh
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D000818:Animals; D000077465:Cabergoline; D002118:Calcium / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D004873:Ergolines / Q000494:pharmacology; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018491:Dopamine Agonists; D004873:Ergolines; D054439:Ghrelin; D017448:Receptors, Dopamine D2; D054440:Receptors, Ghrelin; D019257:Quinpirole; D000077465:Cabergoline; D002118:Calcium