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Genetic variations in human G protein-coupled receptors: implications for drug therapy
1Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco CA 94143-0446, USA. sadee@cgl.ucsf.edu
Abstract:
Numerous genes encode G protein-coupled receptors (GPCRs)-a main molecular target for drug therapy. Estimates indicate that the human genome contains approximately 600 GPCR genes. This article addresses therapeutic implications of sequence variations in GPCR genes. A number of inactivating and activating receptor mutations have been shown to cause a variety of (mostly rare) genetic disorders. However, pharmacogenetic and pharmacogenomic studies on GPCRs are scarce, and therapeutic relevance of variant receptor alleles often remains unclear. Confounding factors in assessing the therapeutic relevance of variant GPCR alleles include 1) interaction of a single drug with multiple closely related receptors, 2) poorly defined binding pockets that can accommodate drug ligands in different orientations or at alternative receptor domains, 3) possibility of multiple receptor conformations with distinct functions, and 4) multiple signaling pathways engaged by a single receptor. For example, antischizophrenic drugs bind to numerous receptors, several of which might be relevant to therapeutic outcome. Without knowing accurately what role a given receptor subtype plays in clinical outcome and how a sequence variation affects drug-induced signal transduction, we cannot predict the therapeutic relevance of a receptor variant. Genome-wide association studies with single nucleotide polymorphisms could identify critical target receptors for disease susceptibility and drug efficacy or toxicity.
Insights
Sequence variations in G protein-coupled receptors (GPCRs) can cause genetic disorders, but their therapeutic implications are often unclear. Further research is needed to understand how these genetic variations impact drug efficacy and toxicity.
Area of Science:
- Pharmacology
- Genetics
- Molecular Biology
Background:
- G protein-coupled receptors (GPCRs) are a major class of drug targets, with approximately 600 genes in the human genome.
- Sequence variations (mutations) in GPCR genes are linked to various genetic disorders, though often rare.
- The therapeutic relevance of variant GPCR alleles is frequently uncertain due to complex biological factors.
Purpose of the Study:
- To explore the therapeutic implications of sequence variations in G protein-coupled receptor (GPCR) genes.
- To highlight the challenges in assessing the clinical significance of genetic variations in GPCRs.
- To emphasize the need for advanced genetic studies in understanding drug response.
Main Methods:
- Review of existing literature on GPCR mutations and genetic disorders.
- Discussion of confounding factors in pharmacogenetic and pharmacogenomic studies of GPCRs.
- Exploration of the potential of genome-wide association studies (GWAS) with single nucleotide polymorphisms (SNPs).
Main Results:
- GPCR gene variations can lead to inactivating or activating mutations causing genetic disorders.
- Pharmacogenetic studies on GPCRs are limited, leaving the therapeutic relevance of variant alleles unclear.
- Complexities such as drug-receptor interactions, binding pockets, receptor conformations, and signaling pathways complicate assessment.
Conclusions:
- Accurate prediction of therapeutic relevance for GPCR variants requires understanding their role in clinical outcomes and drug-induced signaling.
- Genome-wide association studies (GWAS) hold promise for identifying key GPCRs related to disease susceptibility and drug response.
- Further research is crucial to elucidate the impact of GPCR genetic variations on drug efficacy and toxicity.