PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Rediger, A.* ; Piechowski, C.L.* ; Yi, C.-X.* ; Tarnow, P.* ; Strotmann, R.* ; Grüters, A.* ; Krude, H.* ; Schöneberg, T.* ; Tschöp, M.H. ; Kleinau, G.* ; Biebermann, H.*

Mutually opposite signal modulation by hypothalamic heterodimerization of ghrelin and melanocortin-3 receptors.

J. Biol. Chem. 286, 39623-39631 (2011)
DOI PMC
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
Interaction and cross-talk of G-protein-coupled receptors (GPCRs) are of considerable interest because an increasing number of examples implicate a profound functional and physiological relevance of homo- or hetero-oligomeric GPCRs. The ghrelin (growth hormone secretagogue receptor (GHSR)) and melanocortin-3 (MC3R) receptors are both known to have orexigenic effects on the hypothalamic control of body weight. Because in vitro studies indicate heterodimerization of GHSR and MC3R, we investigated their functional interplay. Combined in situ hybridization and immunohistochemistry indicated that the vast majority of GHSR-expressing neurons in the arcuate nucleus also express MC3R. In vitro coexpression of MC3R and GHSR promoted enhanced melanocortin-induced intracellular cAMP accumulation compared with activation of MC3R in the absence of GHSR. In contrast, agonist-independent basal signaling activity and ghrelin-induced signaling of GHSR were impaired, most likely due to interaction with MC3R. By taking advantage of naturally occurring GHSR mutations and an inverse agonist for GHSR, we demonstrate that the observed enhanced MC3R signaling capability depends directly on the basal activity of GHSR. In conclusion, we demonstrate a paradigm-shifting example of GPCR heterodimerization allowing for mutually opposite functional influence of two hypothalamic receptors controlling body weight. We found that the agonist-independent active conformation of one GPCR can determine the signaling modalities of another receptor in a heterodimer. Our discovery also implies that mutations within one of two interacting receptors might affect both receptors and different pathways simultaneously. These findings uncover mechanisms of important relevance for pharmacological targeting of GPCR in general and hypothalamic body weight regulation in particular.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
0.000
1.333
41
82
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Sprache englisch
Veröffentlichungsjahr 2011
HGF-Berichtsjahr 0
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 286, Heft: 45, Seiten: 39623-39631 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502200-001
PubMed ID 21940628
DOI 10.1074/jbc.M111.287607
Erfassungsdatum 2011-12-31
[➜Korrektur melden]