Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization
Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization
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DOI：
10.1210/me.2015-1147
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发表时间：
2016-04-01
影响因子：
--
通讯作者：
Murtha, Amy P.
中科院分区：
文献类型：
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作者：
Grotegut, Chad A.;Mao, Lan;Murtha, Amy P.
催产素是一种有效的子宫收缩剂，临床上用于引产和引产，以及预防和治疗产后出血。催产素通过激活催产素受体（OXTR）增加子宫收缩力，OXTR是G蛋白偶联受体家族的一员，易于分子脱敏。催产素结合后，OXTR被G蛋白偶联受体激酶（GRK）家族的成员磷酸化，这允许募集β-抑制蛋白、受体内化和脱敏。根据先前的体外分析，OXTR对钙信号传导的脱敏是由GRK 6介导的。本研究的目的是确定GRK 6在介导子宫收缩力中的作用。在这里，我们证明了子宫GRK 6水平在怀孕中增加，并使用遥测设备来测量分娩过程中活小鼠子宫收缩力的变化，表明缺乏GRK 6的小鼠与野生型或GRK 5敲除小鼠相比，在自发和催产素诱导的分娩过程中产生增强的子宫收缩力的表型。此外，观察到的收缩性增强与高足月死胎率相关。最后，使用异源体外模型，我们表明，β-抑制蛋白招聘的OXTR，这是必要的同源OXTR脱敏，是依赖于GRK 6。我们的研究结果表明，GRK 6介导的OXTR脱敏在劳动是必要的正常子宫收缩模式和最佳的胎儿结局。
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 beta-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 beta-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.