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Internalization and Desensitization of the Oxytocin Receptor Is Inhibited by Dynamin and Clathrin Mutants in Human Embryonic Kidney 293 Cells

University of Bristol (M.P.S., V.J.A., A.L.B.) Clinical Sciences South Bristol, Division of Obstetrics and Gynaecology, St. Michael’s Hospital, Bristol BS2 8EG, United Kingdom; University of Bristol (S.J.M., E.K.), Department of Pharmacology, School of Medical Sciences, Bristol BS8 1TD, United Kingdom; and University of Bristol (C.A.M.), Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Bristol BS1 3NY, United Kingdom

Address all correspondence and requests for reprints to: M. P. Smith, University of Bristol, Clinical Sciences South Bristol, Division of Obstetrics and Gynaecology, St. Michael’s Hospital, Southwell Street, Bristol BS2 8EG, United Kingdom. E-mail: Mike.smith{at}bris.ac.uk.

Oxytocin (OT) has long been used as an uterotonic during labor management in women, and yet responses to OT infusion remain variable and unpredictable among patients. The investigation of oxytocin receptor (OTR) regulation will benefit labor management, because the clinical practice of continuous iv infusion of OT is not optimal. As with other G protein-coupled receptors, it is likely that the OTR internalizes and/or desensitizes upon continuous agonist exposure. The mechanisms by which this might occur, however, are unclear. Here we explore OTR internalization and desensitization in human embryonic kidney cells by utilizing inhibitors of heterologous second messenger systems and recently available mutant cDNA constructs. We report rapid and extensive internalization and desensitization of the OTR upon agonist exposure. Internalization was unaffected by inhibitors of protein kinase C or Ca²⁺ calmodulin-dependant kinase II but was significantly reduced after transfection with dominant-negative mutant cDNAs of G protein-coupled receptor kinase 2, ß-Arrestin2, Dynamin, and Eps15 (a component of clathrin-coated pits). Moreover, desensitization of the OTR, measured by a calcium mobilization assay, was also inhibited by the aforementioned cDNA constructs. Thus, our data demonstrate, for the first time, the importance of the classical clathrin-mediated pathway during agonist-induced OTR internalization and desensitization.

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