Dehkhoda, F.Ringuet, M.T.Whitfield, E.A.Mutunduwe, K.Whelan, F.Nowell, C.J.Misganaw, D.Xu, Z.Piper, N.B.C.Clark, R.J.Hossain, M.A.Fothergill, L.J.McDougall, S.J.Furness, J.B.Furness, S.G.B.2025-09-222025-09-222025Molecular Cell, 2025; 85(11):2246-22601097-27651097-4164https://hdl.handle.net/2440/147488Changes in cellular output from one G protein-coupled receptor in another’s presence have been attributed to dimerization and/or signal crosstalk. However, data distinguishing models are often lacking, and, in many cases, the molecular basis remains controversial. One such interaction is the reversal, inhibition to excitation, at the dopamine D2 receptor in the ghrelin receptor’s presence in the spinal defecation center. This reversal is required for the physiological control of defecation, where dopamine is the relevant neurotransmitter. Using native neurons from mice and recombinant cells, we show that this reversal of dopamine D2 activity occurs downstream of calcium mobilization through a dominant signaling switch. Our results show that this reversal is a consequence of the ghrelin receptor’s constitutive activity, where neither its agonism nor dimerization with the D2 receptor is required, in the systems tested. Dependence on constitutive activity may account for conservation of central-nervous-system ghrelin receptor in the absence of endogenous agonist.en© 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.NeuronsAnimalsMice, Inbred C57BLHumansMiceCalciumDopamineReceptors, Dopamine D2Signal TransductionReceptors, GhrelinHEK293 CellsNeuronsAnimalsMice, Inbred C57BLHumansMiceCalciumDopamineReceptors, Dopamine D2Signal TransductionReceptors, GhrelinHEK293 CellsJournal article10.1016/j.molcel.2025.05.005741226Whelan, F. [0000-0002-0791-6850]