Genetic variations in human G protein-coupled receptors: Implications for drug therapy
Journal Title: The AAPS Journal - Year 2001, Vol 3, Issue 3
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.
Authors and Affiliations
Wolfgang Sadee, Elen Hoeg, Julie Lucas, Danxin Wang
Keywords
Related Articles
- EP ID EP682065
- DOI 10.1208/ps030322
- Views 93
- Downloads 0
Prediction of Biliary Excretion in Rats and Humans Using Molecular Weight and Quantitative Structure–Pharmacokinetic Relationships
The aims were (1) to evaluate the molecular weight (MW) dependence of biliary excretion and (2) to develop quantitative structure–pharmacokinetic relationships (QSPKR) to predict biliary clearance (CLb) and perce...
Role of Public Standards in the Safety and Efficacy of Biologic Medicines
In this report, we emphasize the importance of public monographs with reference materials, coupled with careful process and change control and attention to GMPs, as a means of advancing access to good quality, safe, and...
Performance of Methods for Handling Missing Categorical Covariate Data in Population Pharmacokinetic Analyses
The online version of this article (doi:10.1208/s12248-012-9373-2) contains supplementary material, which is available to authorized users.
Mesenchymal Stromal/Stem Cell and Minocycline-Loaded Hydrogels Inhibit the Growth of Staphylococcus aureus that Evades Immunomodulation of Blood-Derived Leukocytes
The online version of this article (doi:10.1208/s12248-015-9728-6) contains supplementary material, which is available to authorized users.
Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation
The online version of this article (doi:10.1208/s12248-015-9803-z) contains supplementary material, which is available to authorized users.