Constitutive ghrelin receptor activity enables reversal of dopamine D2 receptor signaling
Date
2025
Authors
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.
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Journal article
Citation
Molecular Cell, 2025; 85(11):2246-2260
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Farhad Dehkhoda, Mitchell T. Ringuet, Emily A. Whitfield, Keith Mutunduwe, Fiona Whelan, Cameron J. Nowell, Desye Misganaw, Zheng Xu, Noah B.C. Piper, Richard J. Clark, Mohammed Akhter Hossain, Linda J. Fothergill, Stuart J. McDougall, John B. Furness, and Sebastian G.B. Furness
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Abstract
Changes 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.
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