Resistance of the dopamine D4 receptor to agonist-induced internalization and degradation |
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| Authors: | Anneleen Spooren Pieter Rondou Katarzyna Debowska Béatrice Lintermans Linda Vermeulen Bart Samyn Kamila Skieterska Griet Debyser Bart Devreese Peter Vanhoenacker Urszula Wojda Guy Haegeman Kathleen Van Craenenbroeck |
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| Affiliation: | 1. Mary D. Allen Laboratory for Vision Research, USC Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, 2250 Alcazar Street, Clinical Science Annex 215, Los Angeles, CA 90033, USA;2. Department of Anatomy, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea;3. Department of Biomedical Engineering, University of Southern California Viterbi School of Engineering, 1042 Downey Way, Los Angeles, CA 90089-1111, USA;4. Laboratory of GPCR Expression and Signal Transduction (L-GEST), Ghent University—UGent, K.L. Ledeganckstraat 35, B-9000 Gent, Belgium;5. Department of Cell & Neurobiology, Keck School of Medicine of the University of Southern California, 2250 Alcazar Street, Clinical Science Center 135H, Los Angeles, CA 90033, USA;1. Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, UK;2. Department of Physiology and Biochemistry, University of Malta, Malta;1. Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;2. Laboratory for Clinical Neuroscience, Centre for Biomedical Technology, Technical University of Madrid, Spain;3. Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany |
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| 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 β-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. |
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