ISSN 1470-3947 (print)
ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology

Published by BioScientifica
Endocrine Abstracts (2012) 29 P1197 
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Signalling properties of the melanocortin 3 receptor are modified by interaction with different ghrelin receptor variants in heterodimers

C. Piechowski, H. Krude, A. Grüters, G. Kleinau & H. Biebermann

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It is a widely accepted concept that G-protein-coupled receptors (GPCRs) are able to form homo- and heterodimers. The physiological relevance of these interactions is of utmost importance.

Recently, we demonstrated that due to co-expression of two key players of hypothalamic body weight regulation, the melanocortin 3 receptor (MC3R) and ghrelin receptor (GHSR), signalling of the MC3R is enhanced (hyperstimulation) as compared to activation of MC3R alone. By using two naturally occurring GHSR mutations (GHSR-A204E, GHSR-F279L) that silence the basal ligand independent activity we showed that the basally active conformation of GHSR is a crucial factor for modified signalling properties in MC3R/GHSR heterodimers.

The aim of this study was to confirm these previous findings by investigation of further naturally occurring GHSR-mutants in co-expression studies with MC3R.

We tested seven already published GHSR variants. Most of these mutations lead to a decreased ligand independent activity and/or to a decreased cell surface expression of GHSR. We measured Gs-induced cAMP accumulation of the co-expressed MC3R and the GHSR-mutants in COS-7 cells after stimulation with 1 μM α-MSH.

The co-expression of six tested GHSR-mutants with the MC3R and α-MSH challenge prevented MC3R hyperstimulation in contrast to the MC3R co-expressed with the GHSR-WT. Only one GHSR-mutant resemble the characteristic MC3R/GHSR hyperstimulation.

Taken together, by testing seven GHSR-mutants we here show that our initial finding of the importance of high basal GHSR activity in a heterodimeric constellation with MC3R is a general phenomenon and that specific GHSR variants almost always modulating MC3R signalling in heterodimers.

This study therefore gives general pathological implications and mechanistic insights into the role of GHSR and MC3R in the appetite regulation by interactive mutual effects on each other. Finally, our study support that elevated basal signalling activity is of high importance to understand the signalling network of GPCRs.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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