Abstract
G protein-coupled receptors (GPCRs) are the largest family of signaling proteins and the most common therapeutic targets. In the last 2 decades, impressive progress in the understanding of GPCR function has been achieved, driven largely 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 human embryonic kidney 293 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 extrapolation from one receptor to another is as likely to be misleading as illuminating. Further progress in the field requires careful analysis of the regulation of individual GPCR subtypes in defined cellular context. In this issue of Molecular Pharmacology, Luo et al. (p. 338) describe a complex pattern of the regulation of M3 muscarinic receptor signaling.