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Engineering the melanocortin-4 receptor to control constitutive and ligand-mediated g(s) signaling in vivo

Academic Article
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Overview

authors

  • Srinivasan, Supriya
  • Santiago, P.
  • Lubrano, C.
  • Vaisse, C.
  • Conklin, B. R.

publication date

  • August 2007

journal

  • PLoS One  Journal

abstract

  • 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 G protein-mediated signaling events that underlie a specific physiological response. To increase our understanding of these processes, we sought to gain control of the timing and specificity of G(s) signaling in vivo. We used naturally occurring human mutations to develop two G(s)-coupled engineered receptors that respond solely to a synthetic ligand (RASSLs). Our G(s)-coupled RASSLs are based on the melanocortin-4 receptor, a centrally expressed receptor that plays an important role in the regulation of body weight. These RASSLs are not activated by the endogenous hormone alpha-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 G(s) pathway in vivo. These RASSLs can be used to activate G(s) signaling in any tissue, but would be particularly useful for analyzing downstream events that mediate body weight regulation in mice. Our study also demonstrates the use of human genetic variation for protein engineering.

subject areas

  • Amino Acid Sequence
  • Cell Line
  • Cell Membrane
  • Cyclic AMP
  • Heterozygote
  • Humans
  • Kidney
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Obesity
  • Point Mutation
  • Protein Conformation
  • Protein Engineering
  • Receptor, Melanocortin, Type 4
  • Tetrahydroisoquinolines
  • Transfection
  • Triazoles
  • alpha-MSH
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Identity

PubMed Central ID

  • PMC1930153

International Standard Serial Number (ISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0000668

PubMed ID

  • 17668051
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Additional Document Info

start page

  • e668

volume

  • 2

issue

  • 8

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