Neuron 73, 317–332 (2012)

Credit: A. KERN AND R. SMITH

The G protein–coupled receptors growth hormone secretagogue receptor 1a (GHSR1a) and dopamine receptor subtype-2 (DRD2) are expressed in the mammalian brain and are linked to the anorexigenic response. However, the mode of action of GHSR1a is unknown, as its ligand ghrelin is barely detected in the brain. Now, Kern et al. provide evidence that unliganded GHSR1a allosterically modifies DRD2, affecting dopamine-mediated activation. Experiments in cell lines and primary neurons showed that expression of GHSR1a along with DRD2 was necessary for dopamine-induced Ca2+ mobilization. However, the downstream components of GHSR1a signaling were not necessary for DRD2 pathway activation, pointing to an interaction between the receptors rather than pathway crosstalk. Indeed, time-resolved fluorescence resonance energy transfer assays and confocal microscopy demonstrated that GHSR1a and DRD2 localized together into receptor heteromers at the cell surface and that alterations in the GHSR1a conformation, either by mutations or by treatment with antagonists, compromised DRD2-induced Ca2+ mobilization. The authors verified the presence of endogenous GHSR1a-DRD2 heteromers in the hypothalamus of wild-type but not Ghsr−/− mice. In further support of a physiological role for the GHSR1a-DRD2 heteromers, treatment of wild-type or ghrelin−/− mice with a DRD2 agonist resulted in anorexia, whereas the drug effect was blunted in Ghsr−/− mice. Conclusively, these results demonstrate that GPCR heteromer formation provides a new mechanism for controlling downstream signaling.