Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism

Neuron. 2012 Jan 26;73(2):317-32. doi: 10.1016/j.neuron.2011.10.038.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cabergoline
  • Calcium / metabolism
  • Dopamine Agonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Eating / drug effects*
  • Ergolines / pharmacology
  • Ghrelin / genetics
  • Ghrelin / metabolism*
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism*
  • Quinpirole / pharmacology
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Ghrelin / genetics
  • Receptors, Ghrelin / metabolism*
  • Signal Transduction / drug effects


  • Dopamine Agonists
  • Ergolines
  • Ghrelin
  • Receptors, Dopamine D2
  • Receptors, Ghrelin
  • Quinpirole
  • Cabergoline
  • Calcium