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Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization.
- Source :
-
Molecular endocrinology (Baltimore, Md.) [Mol Endocrinol] 2016 Apr; Vol. 30 (4), pp. 455-68. Date of Electronic Publication: 2016 Feb 17. - Publication Year :
- 2016
-
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.
- Subjects :
- Animals
Female
G-Protein-Coupled Receptor Kinases metabolism
Gene Expression
HEK293 Cells
Humans
MAP Kinase Signaling System
Male
Mice, Inbred C57BL
Mice, Knockout
Placenta metabolism
Placenta pathology
Pregnancy
Stillbirth
Up-Regulation
Uterus metabolism
G-Protein-Coupled Receptor Kinases genetics
Receptors, Oxytocin metabolism
Uterine Contraction
Uterus physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1944-9917
- Volume :
- 30
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular endocrinology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 26886170
- Full Text :
- https://doi.org/10.1210/me.2015-1147