Received for publication May 20, 2008.
Revised May 23, 2008.
Accepted for publication May 27, 2008.

Rich tapestry of GPCR signaling and regulatory mechanisms (Relates to article by Luo, et al., FastForward 3April 08)

Abstract

G protein-coupled receptors (GPCRs) are the largest family of signaling proteins and the most common therapeutic targets. In the last two decades, an impressive progress in the understanding of GPCR function has been achieved, largely driven by the idea of similarity of the molecular mechanisms underlying their signaling and regulation. However, recent comprehensive studies of signaling and trafficking of several GPCR subtypes, including endogenous M3 muscarinic and H1 histamine receptor and expressed cysteinyl leukotriene type 1 receptor in HEK293 cells, clearly demonstrate that each receptor is regulated by a unique set of molecular mechanisms involving different players. These data indicate that the "gold mine" of similarities is nearly exhausted, and that uncritical extrapolation from one receptor to another is more likely to be misleading than illuminating. Further progress in the field requires careful analysis of the regulation of individual GPCR subtypes in defined cellular context.

Key words: Muscarinic cholinergic, Gq/11 family, G protein regulation, RGS proteins, Desensitization/uncoupling, Sequestration/Internalization, GRKs, barrestins, Phosphorylation/Dephosphorylation