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Open Access Publications from the University of California

Engineering the melanocortin-4 receptor to control constitutive and ligand-mediated Gssignaling in vivo

  • Author(s): Srinivasan, S
  • Santiago, P
  • Lubrano, C
  • Vaisse, C
  • Conklin, BR
  • et al.

The molecular and functional diversity of G protein-coupled receptors is essential to many physiological processes. However, this diversity presents a significant challenge to understanding the 6 protein-mediated signaling events that underlie a specific physiological response. To increase our understanding of these processis we sought to gain control of the timing and specificity of Gssignaling in vivo. We used naturally occurring human mutations to develop two Gs-coupled engineered receptors that respond solely to a synthetic ligand (RASSLs). Our Gs-coupled RASSLs are based on the melanocortin-4 receptor a centrally expressed receptor that plays an important role in the regulation of body weiqht. These RASSLs are not activated by the endogenous hormone α-melanocyte-stimulating hormone but respond potently to a selective synthetic ligand tetrahydroisoquinoline. The RASSL variants reported here differ in their intrinsic basal activities, allowing the separation of the effects of basal signaling from ligand-mediated activation of the Gspathway in vivo. These RASSLs can be used to activate Gssignaling in any tissue, but would be particularly useful for analyzing downstream events that mediate body weight reguration in mice. Our study also demonstrates the use of human genetic variation for protein engineering. © 2007 Srinivasan et al.

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