Historical review: a brief history and personal retrospective of seven-transmembrane receptors.
Pharmacologists have studied receptors for more than a century but a molecular understanding of their properties has emerged only during the past 30-35 years. In this article, I provide a personal retrospective of how developments and discoveries primarily during the 1970s and 1980s led to current concepts about the largest group of receptors, the superfamily of seven-transmembrane (7TM) receptors [also known as G-protein-coupled receptors (GPCRs)]. Significant technical advances such as the development of methods for radioligand binding, solubilization and purification of the beta(2)-adrenoceptor and other adrenoceptors led to the cloning of receptor genes and the discovery of their 7TM architecture and homology with rhodopsin. A universal mechanism of receptor regulation by G-protein-coupled receptor kinases (GRKs) and arrestins, originally discovered as a means of "desensitizing" G-protein-mediated second-messenger generation, was subsequently found to mediate both receptor endocytosis and activation of a growing list of signaling pathways such as those involving mitogen-activated protein kinases. Numerous opportunities for novel therapeutics should emerge from current and future research on 7TM receptor biology.
Lefkowitz
Robert J
RJ
Howard Hughes Medical Institute, James B. Duke Professor of Medicine, Duke University Medical Center, Room 468, CARL Bldg., Research Drive, DUMC Box 3821, Durham, NC 27710, USA. lefko001@receptor-biol.duke.edu
D000818:Animals; D049673:History, 20th Century; D006801:Humans; D008565:Membrane Proteins / Q000266:history* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000266:history* / Q000502:physiology
D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled