title: Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization.
abstract: Oxytocin is a potent uterotonic agent and is used clinically for induction and augmentation of labor, as well as for prevention and treatment of postpartum hemorrhage. Oxytocin increases uterine contractility by activating the oxytocin receptor (OXTR), a member of the G protein-coupled receptor family, which is prone to molecular desensitization. After oxytocin binding, the OXTR is phosphorylated by a member of the G protein-coupled receptor kinase (GRK) family, which allows for recruitment of β-arrestin, receptor internalization, and desensitization. According to previous in vitro analyses, desensitization of calcium signaling by the OXTR is mediated by GRK6. The objective of this study was to determine the role of GRK6 in mediating uterine contractility. Here, we demonstrate that uterine GRK6 levels increase in pregnancy and using a telemetry device to measure changes in uterine contractility in live mice during labor, show that mice lacking GRK6 produce a phenotype of enhanced uterine contractility during both spontaneous and oxytocin-induced labor compared with wild-type or GRK5 knockout mice. In addition, the observed enhanced contractility was associated with high rates of term stillbirth. Lastly, using a heterologous in vitro model, we show that β-arrestin recruitment to the OXTR, which is necessary for homologous OXTR desensitization, is dependent on GRK6. Our findings suggest that GRK6-mediated OXTR desensitization in labor is necessary for normal uterine contractile patterns and optimal fetal outcome.
authors.affiliation: Departments of Obstetrics and Gynecology (C.A.G., S.L.P., G.K.S., R.P.H., A.P.M.) and Medicine (L.M.), Duke University, Durham, North Carolina 27710.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Grotegut
authors.affiliation: Departments of Obstetrics and Gynecology (C.A.G., S.L.P., G.K.S., R.P.H., A.P.M.) and Medicine (L.M.), Duke University, Durham, North Carolina 27710.
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.affiliation: Departments of Obstetrics and Gynecology (C.A.G., S.L.P., G.K.S., R.P.H., A.P.M.) and Medicine (L.M.), Duke University, Durham, North Carolina 27710.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Pierce
authors.affiliation: Departments of Obstetrics and Gynecology (C.A.G., S.L.P., G.K.S., R.P.H., A.P.M.) and Medicine (L.M.), Duke University, Durham, North Carolina 27710.
authors.forename: Geeta K
authors.initials: GK
authors.lastname: Swamy
authors.affiliation: Departments of Obstetrics and Gynecology (C.A.G., S.L.P., G.K.S., R.P.H., A.P.M.) and Medicine (L.M.), Duke University, Durham, North Carolina 27710.
authors.forename: R Phillips
authors.initials: RP
authors.lastname: Heine
authors.affiliation: Departments of Obstetrics and Gynecology (C.A.G., S.L.P., G.K.S., R.P.H., A.P.M.) and Medicine (L.M.), Duke University, Durham, North Carolina 27710.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Murtha
mesh_terms: D000818:Animals; D005260:Female; D054768:G-Protein-Coupled Receptor Kinases / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D018045:Receptors, Oxytocin / Q000378:metabolism*; D050497:Stillbirth; D015854:Up-Regulation; D014590:Uterine Contraction; D014599:Uterus / Q000378:metabolism / Q000503:physiopathology*
chemical_list: C576074:OXTR protein, mouse; D018045:Receptors, Oxytocin; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6