Pharmacogenomic and Structural Analysis of Constitutive G Protein–Coupled Receptor Activity

Martine J. Smit, Henry F. Vischer, Remko A. Bakker, Aldo Jongejan, Henk Timmerman, Leonardo Pardo, Rob Leurs
2007 Annual Review of Pharmacology and Toxicology  
G-protein coupled receptors (GPCRs) respond to a chemically diverse plethora of signal transduction molecules. The notion that GPCRs also signal without an external chemical trigger, i.e. in a constitutive or spontaneous manner, resulted in a paradigm shift in the field of GPCR pharmacology. With the recognition of constitutive GPCR activity and the fact that GPCR binding and signaling can be strongly affected by a single point mutation, GPCR pharmacogenomics obtained a lot of attention. For a
more » ... f attention. For a variety of GPCRs, point mutations have been convincingly linked to human disease. Mutations within conserved motifs, known to be involved in GPCR activation, might explain the properties of some naturally occurring constitutively active GPCR variants linked to disease. A brief history historical introduction to the present concept of constitutive receptor activity is given and the pharmacogenomic and the structural aspects of constitutive receptor activity are described.
doi:10.1146/annurev.pharmtox.47.120505.105126 pmid:17029567 fatcat:qhefvyj3yvbnrbemjygxftsxfe