title: Resistance of the dopamine D4 receptor to agonist-induced internalization and degradation.
abstract: Dopamine receptors are G-protein-coupled receptors involved in the control of motivation, learning, and fine-tuning of motor movement, as well as modulation of neuroendocrine signalling. Stimulation of G-protein-coupled receptors normally results in attenuation of signalling through desensitization, followed by internalization and down-regulation of the receptor. These processes allow the cell to regain homeostasis after exposure to extracellular stimuli and offer protection against excessive signalling. Here, we have investigated the agonist-mediated attenuation properties of the dopamine D4 receptor. We found that several hallmarks of signal attenuation such as receptor phosphorylation, internalization and degradation showed a blunted response to agonist treatment. Moreover, we did not observe recruitment of beta-arrestins upon D4 receptor stimulation. We also provide evidence for the constitutive phosphorylation of two serine residues in the third intracellular loop of the D4 receptor. These data demonstrate that, when expressed in CHO, HeLa and HEK293 cells, the human D4 receptor shows resistance to agonist-mediated internalization and down-regulation. Data from neuronal cell lines, which have been reported to show low endogenous D4 receptor expression, such as the hippocampal cell line HT22 and primary rat hippocampal cells, further support these observations.
authors.affiliation: Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Ghent University-UGent, K.L. Ledeganckstraat 35, B-9000 Gent, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Spooren
authors.forename: Pieter
authors.initials: P
authors.lastname: Rondou
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Debowska
authors.forename: Béatrice
authors.initials: B
authors.lastname: Lintermans
authors.forename: Linda
authors.initials: L
authors.lastname: Vermeulen
authors.forename: Bart
authors.initials: B
authors.lastname: Samyn
authors.forename: Kamila
authors.initials: K
authors.lastname: Skieterska
authors.forename: Griet
authors.initials: G
authors.lastname: Debyser
authors.forename: Bart
authors.initials: B
authors.lastname: Devreese
authors.forename: Peter
authors.initials: P
authors.lastname: Vanhoenacker
authors.forename: Urszula
authors.initials: U
authors.lastname: Wojda
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.forename: Kathleen
authors.initials: K
authors.lastname: Van Craenenbroeck
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D009474:Neurons / Q000166:cytology; D010766:Phosphorylation; D021381:Protein Transport; D051381:Rats; D050638:Receptors, Dopamine D4 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C493599:DRD4 protein, human; D000071557:beta-Arrestins; D050638:Receptors, Dopamine D4