Genetic Vulnerability of GPCRs: A Call to Action

Abstract

G-protein-coupled receptors (GPCRs) are the targets for many drugs, but the response shows interindividual variability. The 'one-drug-fits-all' approach has been challenged by evidence showing multiple human genetic variants of GPCRs. Identification and characterization of GPCR variants must be undertaken for rational, personalized, and economically sound prescribing practices.

Keywords: G protein; asthma; coupling; heart failure; mutation; polymorphism.

Figure 1. GPCR structure, clinical variability, and a variant phenotyping scheme

A) The typography of a GPCR, depicting the TMD segments, the extracellular loops (ECL), intracellular loops (ICL), and amino-terminal (extracellular) and carboxy-terminal (intracellular) regions. Each circle represents an amino-acid. Shown is the β₂AR. B) The distribution of clinical responses grouped by the magnitude of the response. The data represent a hypothetical example. C) Variant discovery from a multiethnic DNA repository is utilized to ascertain potential functional implications. Cloning or mutagenesis is used to make the variant cDNA for transfection of model cells to ascertain basic pharmacology. Additional studies of pharmacology and physiology can also be obtained using genetically altered mice, human tissue, or human physiological studies. Taken together, they can lead to a hypothesis-driven clinical trial (prospective or retrospective) which may show associations between variant and drug response. Data can also provide leads for additional variant screening of other genes.