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Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese

Zhen-Chuan Fan1, Ya-Xiong Tao

  • 1Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849-5519, USA.

Journal of Cellular and Molecular Medicine
|March 21, 2009
PubMed

Insights

Melanocortin-4 receptor (MC4R) gene mutations cause obesity. Six of ten novel MC4R mutants showed reduced cell surface expression. A pharmacological chaperone therapy shows promise for treating MC4R-related obesity.

Area of Science:

  • Genetics and Molecular Biology
  • Endocrinology
  • Pharmacology

Background:

  • The melanocortin-4 receptor (MC4R) is a key regulator of energy homeostasis.
  • Mutations in the MC4R gene represent the most common monogenic cause of human obesity.
  • Over 130 MC4R mutations have been identified, necessitating detailed functional characterization.

Purpose of the Study:

  • To functionally characterize 10 novel human MC4R (hMC4R) mutants.
  • To investigate the impact of these mutations on receptor expression, binding, and signaling.
  • To explore potential therapeutic strategies for MC4R mutations causing intracellular retention.

Main Methods:

  • Flow cytometry was used to assess cell surface expression of hMC4R mutants.
  • Binding assays were performed to evaluate agonist and antagonist binding affinities.
  • Signaling assays, including cAMP production, were conducted to assess receptor function.
  • The effect of an MC4R inverse agonist (ML00253764) as a pharmacological chaperone was tested on specific mutants.

Main Results:

  • Six of the 10 novel hMC4R mutants (R7C, C84R, S127L, W174C, P230L, F261S) exhibited decreased cell surface expression.
  • Four mutants showed expression levels comparable to wild-type hMC4R.
  • Binding affinities for agonists and agouti-related protein were largely unaffected.
  • One mutant (S136F) was defective in signaling, indicating S136 is crucial for normal receptor function.
  • The inverse agonist ML00253764 acted as a pharmacological chaperone, rescuing intracellularly retained mutants (C84R, W174C) to the cell surface.
  • Rescued mutants demonstrated restored functionality with increased cAMP production.

Conclusions:

  • A significant proportion of novel MC4R mutations lead to reduced cell surface expression, impacting receptor function.
  • Pharmacological chaperones represent a promising therapeutic avenue for obesity linked to MC4R mutations causing intracellular retention.

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