Journal
PLOS ONE
Volume 6, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0024644
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Funding
- Danish Medical Research Council
- European Community [LSHB-CT-2005-518167]
- NovoNordisk Foundation
- Lundbeck Foundation
- AP-Moller Foundation
- Aase and Einer Danielsen Foundation
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Background: The melanocortin 1 receptor (MC1R) constitutes a key regulator of melanism. Consequently, many naturally-occurring MC1R mutations are associated with a change in color. An example is the Glu-to-Lys substitution found at position II: 20/2.60 in the top of transmembrane helix II which has been identified in melanic mice and several other species. This mutation induces a pronounced increase in MC1R constitutive activity suggesting a link between constitutive activity and melanism which is corroborated by the attenuation of alpha-melanocyte stimulating hormone (alpha MSH) induced activation. However, the mechanism by which the mutation induces constitutive activity is currently not known. Methodology/Principal Findings: Here we characterize the constitutive activity, cell surface expression and internalization of the mouse mutant, Mc1r E92K. As previously reported, only positively charged residues at position II: 20/2.60 induced an increase in constitutive activity as measured by cAMP accumulation and CREB activation. Furthermore, the mutation induced a constitutive recruitment of beta-arrestin. This phenomenon is only observed in MC1R, however, as the equivalent mutations in MC2-5R had no effect on receptor signaling. Interestingly, the mutation did not induce constitutive ERK1/2 phosphorylation or increase the internalization rate indicating the constitutive activity to be biased. Finally, to identify regions of importance for the increased constitutive activity of Mc1r E92K, we employed a chimeric approach and identified G102 and L110 in the extracellular loop 1 to be selectively important for the constitutive activity as this, but not alpha MSH-mediated activation, was abolished upon Ala substitution. Conclusions/Significance: It is concluded that the E92K mutation induces an active conformation distinct from that induced by alpha MSH and that the extracellular loop 1 is involved in maintaining this conformational state. In turn, the results suggest that in MC1R, which lacks an extracellular loop 2, the first extracellular loop may play a more prominent role during receptor activation than in general.
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