Neuron
Volume 73, Issue 2, 26 January 2012, Pages 317-332
Journal home page for Neuron

Article
Apo-Ghrelin Receptor Forms Heteromers with DRD2 in Hypothalamic Neurons and Is Essential for Anorexigenic Effects of DRD2 Agonism

https://doi.org/10.1016/j.neuron.2011.10.038Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► GHSR1a and DRD2 form heteromers in vitro and in vivo in hypothalamic neurons ► GHSR1a allosterically modifies DRD2 signaling by Gβγ dependent [Ca2+]i mobilization ► Anorexigenic effects of a DRD2 agonist are dependent upon ghsr expression ► A GHSR1a selective antagonist blocks the anorexigenic effect of a DRD2 agonist

Cited by (0)