Trafficking and signaling of G protein-coupled receptors in the nervous system: implications for disease and therapy.
G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.
Bunnett
Nigel W
NW
Departments of Surgery and Physiology, University of California, San Francisco, 94143-0660, USA.
Cottrell
Graeme S
GS
D017398:Alternative Splicing; D000818:Animals; D019390:Arrestins / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods; D011992:Endosomes / Q000378:metabolism; D054768:G-Protein-Coupled Receptor Kinases / Q000502:physiology; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071557:beta-Arrestins
D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D054768:G-Protein-Coupled Receptor Kinases; D010447:Peptide Hydrolases; D020962:Heterotrimeric GTP-Binding Proteins