title: G protein-coupled receptor kinases as regulators of dopamine receptor functions.
abstract: Actions of the neurotransmitter dopamine in the brain are mediated by dopamine receptors that belong to the superfamily of G protein-coupled receptors (GPCRs). Mammals have five dopamine receptor subtypes, D1 through D5. D1 and D5 couple to Gs/olf and activate adenylyl cyclase, whereas D2, D3, and D4 couple to Gi/o and inhibit it. Most GPCRs upon activation by an agonist are phosphorylated by GPCR kinases (GRKs). The GRK phosphorylation makes receptors high-affinity binding partners for arrestin proteins. Arrestin binding to active phosphorylated receptors stops further G protein activation and promotes receptor internalization, recycling or degradation, thereby regulating their signaling and trafficking. Four non- visual GRKs are expressed in striatal neurons. Here we describe known effects of individual GRKs on dopamine receptors in cell culture and in the two in vivo models of dopamine-mediated signaling: behavioral response to psychostimulants and L-DOPA- induced dyskinesia. Dyskinesia, associated with dopamine super-sensitivity of striatal neurons, is a debilitating side effect of L-DOPA therapy in Parkinson's disease. In vivo, GRK subtypes show greater receptor specificity than in vitro or in cultured cells. Overexpression, knockdown, and knockout of individual GRKs, particularly GRK2 and GRK6, have differential effects on signaling of dopamine receptor subtypes in the brain. Furthermore, deletion of GRK isoforms in select striatal neuronal types differentially affects psychostimulant-induced behaviors. In addition, anti-dyskinetic effect of GRK3 does not require its kinase activity: it is mediated by the binding of its RGS-like domain to Gαq/11, which suppresses Gq/11 signaling. The data demonstrate that the dopamine signaling in defined neuronal types in vivo is regulated by specific and finely orchestrated actions of GRK isoforms.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37221, USA. Electronic address: Eugenia.Gurevich@vanderbilt.edu.
authors.forename: Eugenia V
authors.initials: EV
authors.lastname: Gurevich
authors.affiliation: Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, 199034, Russia; Skolkovo Institute of Science and Technology, Skolkovo, 143025, Moscow, Russia.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37221, USA.
authors.forename: Vsevolod V
authors.initials: VV
authors.lastname: Gurevich
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D006801:Humans; D020734:Parkinsonian Disorders / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D011954:Receptors, Dopamine; D054768:G-Protein-Coupled Receptor Kinases
keywords: Dopamine receptor; Dyskinesia; G protein-coupled receptor kinase; L-DOPA; Parkinson’s disease; Psychostimulants