Constitutive ghrelin receptor activity enables reversal of dopamine D2 receptor signaling

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dc.contributor.authorDehkhoda, F.
dc.contributor.authorRinguet, M.T.
dc.contributor.authorWhitfield, E.A.
dc.contributor.authorMutunduwe, K.
dc.contributor.authorWhelan, F.
dc.contributor.authorNowell, C.J.
dc.contributor.authorMisganaw, D.
dc.contributor.authorXu, Z.
dc.contributor.authorPiper, N.B.C.
dc.contributor.authorClark, R.J.
dc.contributor.authorHossain, M.A.
dc.contributor.authorFothergill, L.J.
dc.contributor.authorMcDougall, S.J.
dc.contributor.authorFurness, J.B.
dc.contributor.authorFurness, S.G.B.
dc.date.issued2025
dc.description.abstractChanges 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.
dc.description.statementofresponsibilityFarhad 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
dc.identifier.citationMolecular Cell, 2025; 85(11):2246-2260
dc.identifier.doi10.1016/j.molcel.2025.05.005
dc.identifier.issn1097-2765
dc.identifier.issn1097-4164
dc.identifier.orcidWhelan, F. [0000-0002-0791-6850]
dc.identifier.urihttps://hdl.handle.net/2440/147488
dc.language.isoen
dc.publisherCell Press
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT2012657
dc.relation.granthttp://purl.org/au-research/grants/arc/FT180100543
dc.rights© 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
dc.source.urihttps://doi.org/10.1016/j.molcel.2025.05.005
dc.subjectNeurons
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectHumans
dc.subjectMice
dc.subjectCalcium
dc.subjectDopamine
dc.subjectReceptors, Dopamine D2
dc.subjectSignal Transduction
dc.subjectReceptors, Ghrelin
dc.subjectHEK293 Cells
dc.subject.meshNeurons
dc.subject.meshAnimals
dc.subject.meshMice, Inbred C57BL
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshCalcium
dc.subject.meshDopamine
dc.subject.meshReceptors, Dopamine D2
dc.subject.meshSignal Transduction
dc.subject.meshReceptors, Ghrelin
dc.subject.meshHEK293 Cells
dc.titleConstitutive ghrelin receptor activity enables reversal of dopamine D2 receptor signaling
dc.typeJournal article
pubs.publication-statusPublished

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