GRKs and arrestins: regulators of migration and inflammation.
In the immune system, signaling by G protein-coupled receptors (GPCRs) is crucial for the activity of multiple mediators, including chemokines, leukotrienes, and neurotransmitters. GPCR kinases (GRKs) and arrestins control GPCR signaling by mediating desensitization and thus, regulating further signal propagation through G proteins. Recent evidence suggests that the GRK-arrestin desensitization machinery fulfills a vital role in regulating inflammatory processes. First, GRK/arrestin levels in immune cells are dynamically regulated in response to inflammation. Second, in animals with targeted deletion of GRKs or arrestins, the progression of various acute and chronic inflammatory disorders, including autoimmunity and allergy, is profoundly affected. Third, chemokine receptor signaling in vitro is known to be tightly regulated by the GRK/arrestin machinery, and even small changes in GRK/arrestin expression can have a marked effect on cellular responses to chemokines. This review integrates data about the role of GRKs and arrestins in inflammation, with results on the molecular mechanism of action of GRKs/arrestins, and describes the pivotal role of GRKs/arrestins in inflammatory processes, with a special emphasis on regulation of chemokine responsiveness.
Vroon
Anne
A
Department of Psychoneuroimmunology, Room KC03.063.0, Lundlaan 6, 3584 EA, Utrecht, The Netherlands.
Heijnen
Cobi J
CJ
Kavelaars
Annemieke
A
D000208:Acute Disease; D000818:Animals; D019390:Arrestins / Q000276:immunology*; D001249:Asthma / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000276:immunology*; D002908:Chronic Disease; D006801:Humans; D007111:Immunity, Cellular; D007249:Inflammation / Q000276:immunology; D015289:Leukotrienes / Q000276:immunology; D018377:Neurotransmitter Agents / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
D019390:Arrestins; D018925:Chemokines; D015289:Leukotrienes; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled