G protein-coupled receptor sorting to endosomes and lysosomes.
The heptahelical G protein-coupled receptors (GPCRs) belong to the largest family of cell surface signaling receptors encoded in the human genome. GPCRs signal to diverse extracellular stimuli and control a vast number of physiological responses, making this receptor class the target of nearly half the drugs currently in use. In addition to rapid desensitization, receptor trafficking is crucial for the temporal and spatial control of GPCR signaling. Sorting signals present in the intracytosolic domains of GPCRs regulate trafficking through the endosomal-lysosomal system. GPCR internalization is mediated by serine and threonine phosphorylation and arrestin binding. Short, linear peptide sequences including tyrosine- and dileucine-based motifs, and PDZ ligands that are recognized by distinct endocytic adaptor proteins also mediate internalization and endosomal sorting of GPCRs. We present new data from bioinformatic searches that reveal the presence of these types of sorting signals in the cytoplasmic tails of many known GPCRs. Several recent studies also indicate that the covalent modification of GPCRs with ubiquitin serves as a signal for internalization and lysosomal sorting, expanding the diversity of mechanisms that control trafficking of mammalian GPCRs.
Marchese
Adriano
A
Department of Pharmacology and Experimental Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA. amarchese@lumc.edu
Paing
May M
MM
Temple
Brenda R S
BR
Trejo
JoAnn
J
D019390:Arrestins / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism*; D010766:Phosphorylation; D021382:Protein Sorting Signals / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D019390:Arrestins; D008024:Ligands; D021382:Protein Sorting Signals; D043562:Receptors, G-Protein-Coupled; D025801:Ubiquitin