Pertussistoxin-sensitive Signalwege von alpha-MSH und AgRP an Melanocortin-4-Rezeptoren
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Philipps-Universität Marburg
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Abstract
The Melanocortin-4 receptor (MC4R) is a G-protein-coupled receptor (GPCR),
which signalling is essential for the control of homeostasis of body weight in the
hypothalamus. Mutations in the MC4R are the most frequent monogenetic cause of
severe adiposity. So far, the signalling of the MC4R has been exclusively attributed to
its coupling to Gs-proteins. The endogenous MC4R-agonist Melanocyt-stimulating
hormone Ð (Ð-MSH) acts anorexigenic by an increase of cAMP-accumulation due
to Gs-activation. Consistent with this finding the D90N-mutation of the MC4R,
which selctively lacks in Gs-coupling is associated with severe obesity. A special cha-
racteristic of the MC4R is the existence of endogenous antagonists: Agouti-related
protein (AgRP) acts orexigenic by an decrease of cAMP-accumulation. This decre-
ase in cAMP-accumulation is independent from the presence of agonists, i.e. AgRP
has autonomous signalling apart from displacement of agonists. This autonomous
signalling of AgRP has been described as inverse agonism, which means the stabi-
lization of a conformation of the receptor with a lower degree of Gs-coupling than
the basal one in absence of an agonist. Interestingly the physiologic relevance and
the detailed mechanism of this signalling are still unknown. For the exploration of
the detailed molecular mechanism of action of Ð-MSH and AgRP at the MC4R,
overexpressing HEK293-cells and endogenous expressing GT1-7-cells were used. G-
protein-activation was examined by GTPÒ35S-assay and the cAMP-accumulation
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6. Abstract
by a cAMP-assay. Surprisingly we found that not only the agonist Ð-MSH but also
the antagonist AgRP activates G-proteins at the MC4R. The G-protein-activation
due to AgRP was PTX-sensitiv, which characterizes the activated G-proteins as
Gi/o. In addition the PTX-sensitiv activation of G-proteins of the Gs-deficient mu-
tation documents the involvement of Gi/o-proteins in the signalling of the MC4R
in general. Conclusively, we could establish the dual coupling of the MC4R to Gs-
and Gi/o-proteins in an endogenous cell system. AgRP is able to activate selectively
Gi/o-proteins and can regulate independently from Ð-MSH the homeostasis of bo-
dy weight. In addition to this important findings for the melanocortin system, the
definition of AgRP as an endogenous biased agonist at an established GPCR has
relevant impact on the understanding of this receptor family in general.
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Dates
Created: 2012Issued: 2012-11-05Updated: 2012-11-05
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Melanocortin-4 receptor
DFG-subjects
Melanocortin-4-Rezeptor
DDC-Numbers
610
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Heling, Dominik Johannes: Pertussistoxin-sensitive Signalwege von alpha-MSH und AgRP an Melanocortin-4-Rezeptoren. : Philipps-Universität Marburg 2012-11-05. DOI: https://doi.org/10.17192/z2012.0970.
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