Research ArticleGPCR SIGNALING

Regulation of G Protein–Coupled Receptor Signaling: Specific Dominant-Negative Effects of Melanocortin 2 Receptor Accessory Protein 2

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Science Signaling  06 Apr 2010:
Vol. 3, Issue 116, pp. ra28
DOI: 10.1126/scisignal.2000593

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Dominating the Response

The signaling of some G protein–coupled receptors (GPCRs) can be modulated by accessory proteins, such as receptor-transporting proteins and receptor activity–modulating proteins. The localization of the melanocortin 2 receptor (MC2R) at the plasma membrane and its signaling depend on MC2R accessory protein (MRAP). MC2R is the receptor for the hormone ACTH, and mutations in MC2R or MRAP cause familial glucocorticoid deficiency. Sebag and Hinkle characterized the effects of a second accessory protein, MRAP2, on the potency of MC2R-mediated responses to ACTH. Although membrane localization of MC2R by MRAP2 was similar to that mediated by MRAP, the affinity of MC2R for ACTH was much lower in the presence of MRAP2 than when MRAP was present. ACTH-dependent generation of cAMP was substantially lower in cells containing MRAP2 than in those containing MRAP. MRAP2 formed homodimers and heterodimers with MRAP, and experiments in which the amount of MRAP2 protein was titrated revealed that it had a dominant-negative effect on MC2R signaling in the presence of MRAP. Such competition between stimulatory and inhibitory accessory proteins may provide therapeutic strategies to modulate receptor signaling.

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