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Inactivating mutations of G protein-coupled receptors and diseases: structure-function insights and therapeutic

Ya-Xiong Tao1

  • 1Department of Anatomy, Physiology and Pharmacology, 213 Greene Hall, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA. taoyaxi@vetmed.auburn.edu

Pharmacology & Therapeutics
|April 18, 2006
PubMed

Insights

Inactivating mutations in G protein-coupled receptors (GPCRs) cause various diseases. This review highlights disease mechanisms, structure-function insights, and therapeutic strategies, particularly pharmacological chaperones for intracellular retention defects.

Area of Science:

  • Molecular Biology
  • Genetics
  • Pharmacology

Background:

  • The discovery of rhodopsin mutations causing retinitis pigmentosa in 1990 marked a turning point in understanding GPCR-related diseases.
  • Significant advancements have been made in elucidating the pathophysiology of diseases linked to inactivating mutations in G protein-coupled receptors (GPCRs).

Purpose of the Study:

  • To compile evidence on the etiologies of over a dozen diseases caused by inactivating GPCR mutations over the past 15 years.
  • To propose a generalized classification scheme for these diseases based on the GPCR life cycle.
  • To review structure-function relationships and therapeutic approaches for GPCR mutants.

Main Methods:

  • Literature review of studies on inactivating GPCR mutations.
  • Analysis of disease mechanisms and GPCR structure-function relationships.
  • Compilation of therapeutic strategies, focusing on pharmacological chaperones.

Main Results:

  • Over a dozen diseases are caused by inactivating GPCR mutations, with intracellular retention being a common defect.
  • Detailed studies of naturally occurring mutations provide insights into GPCR structure-function.
  • Therapeutic approaches are being developed, with pharmacological chaperones showing promise for correcting intracellular retention.

Conclusions:

  • Inactivating GPCR mutations lead to diverse pathologies, offering insights into receptor biology.
  • Understanding GPCR dysfunction is crucial for developing targeted therapies.
  • Pharmacological chaperones represent a promising therapeutic avenue for GPCR-related disorders, especially those involving intracellular retention.

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