Endocrine Abstracts (2006) 11 S69

Gs-independent signalling of melanocortin-4 receptors

T Gudermann & A Breit

Institut of Pharmacology and Toxicology, Philipps-University Marburg, 35043, Marburg, Germany.

Melanocortin receptors (MCR), which belong to the superfamiliy of G protein-coupled receptors (GPCR), are preferentially coupled to Gs proteins and play a major role in the regulation of energy homeostasis. In line with this notion, mutations in the MC4R gene are the most frequent monogenic cause of severe obesity in human beings. Surprisingly, MC4R mutations isolated from obese candidates showed both increased or decreased potency to promote the Gs signalling pathway when overexpressed in HEK-293 cells. Therefore, no clear correlation between the functional alterations found in HEK-293 cells and the dysregulation of the energy homeostasis observed in vivo could be drawn. The MC4R-D90N mutation, which has also been isolated from an obese individual, binds agonists with unchanged high affinity, but promotes no detectable activation of the Gs signalling pathway in HEK-293 cells. Despite of the blunted Gs signalling, agonist binding to the MC4R-D90N mutant induced the recruitment of the adapter protein arrestin when both proteins were overexpressed in HEK-293 cells and agonist-promoted interactions between the MC4R-D90N mutant and arrestin in living cells were monitored by the bioluminescence resonance energy transfer technique. For some GPCRs it has been reported that such arrestin-receptor complexes exhibit the propensity to activate the extracellular-regulated protein kinase (ERK) signalling cascade independent of G protein activity. In line with these observations, HEK-293 cells expressing the MC4R-D90N mutation showed enhanced ERK activity after stimulation with MC4R agonists. MC4R-D90N-mediated activation of the ERK signalling pathway is therefore independent of Gs activity but most possibly depends on the recruitment of arrestin. In summary we conclude that mutations within the MC4R gene lead to the inhibition of the Gs but not of the ERK signalling pathway and that apart from the classical Gs pathway other signalling cascades might contribute to the MC4R-mediated regulation of energy homeostasis.

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