Div. of Maternal-Fetal Medicine, Dept. of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC 27710, USA.
Am J Physiol Endocrinol Metab. 2011 Mar;300(3):E468-77. doi: 10.1152/ajpendo.00390.2010. Epub 2010 Dec 7.
Desensitization of the oxytocin receptor (OXTR) in the setting of prolonged oxytocin exposure may lead to dysfunctional labor, which increases the risk for cesarean delivery, and uterine atony, which may result in postpartum hemorrhage. The molecular mechanism for OXTR desensitization is through the agonist-mediated recruitment of the multifunctional protein β-arrestin. In addition to its desensitizing function, β-arrestins have recently been shown to simultaneously activate downstream signaling. We tested whether oxytocin stimulation promotes β-arrestin-mediated OXTR desensitization in vivo and activates β-arrestin-mediated mitogen-activated protein kinase (MAPK) growth signaling. Uterine muscle strips isolated from wild-type mice exhibited diminished uterine contractility following repeated exposure to oxytocin, whereas uterine muscle strips from β-arrestin-1 and β-arrestin-2 knockout mice showed no desensitization. Utilizing siRNA knockdown of β-arrestin-1 and β-arrestin-2 in HEK-293 cells expressing the OXTR, we demonstrated oxytocin-mediated MAPK signaling that was dependent on β-arrestin-1 and β-arrestin-2. Wild-type and β-arrestin-1 and β-arrestin-2 knockout mice receiving intravenous oxytocin also demonstrated oxytocin-mediated MAPK signaling that was dependent on β-arrestin-1 and β-arrestin-2. Finally, to test the significance of β-arrestin-mediated signaling from the OXTR, HEK-293 cells expressing the OXTR showed β-arrestin-dependent proliferation in a cell migration assay following oxytocin treatment. In conclusion, β-arrestin is a multifunctional scaffold protein that mediates both desensitization of the OXTR, leading to decreases in uterine contractility, and MAPK growth signaling following stimulation by oxytocin. The development of unique OXTR ligands that prevent receptor desensitization may be a novel approach in the treatment of adverse clinical events secondary to prolonged oxytocin therapy.
催产素受体（OXTR）在长时间暴露于催产素的情况下脱敏，可能导致功能失调的分娩，从而增加剖宫产和子宫乏力的风险，这可能导致产后出血。OXTR 脱敏的分子机制是通过多功能蛋白β-arrestin 的激动剂介导募集。除了脱敏功能外，β-arrestin 最近还被证明可以同时激活下游信号。我们测试了催产素刺激是否在体内促进β-arrestin 介导的 OXTR 脱敏，并激活β-arrestin 介导的丝裂原活化蛋白激酶（MAPK）生长信号。从野生型小鼠中分离的子宫肌条在反复暴露于催产素后表现出子宫收缩力减弱，而β-arrestin-1 和β-arrestin-2 敲除小鼠的子宫肌条则没有脱敏。利用 siRNA 敲低表达 OXTR 的 HEK-293 细胞中的β-arrestin-1 和β-arrestin-2，我们证明了依赖于β-arrestin-1 和β-arrestin-2 的催产素介导的 MAPK 信号。接受静脉内催产素的野生型和β-arrestin-1 和β-arrestin-2 敲除小鼠也表现出依赖于β-arrestin-1 和β-arrestin-2 的催产素介导的 MAPK 信号。最后，为了测试 OXTR 中的β-arrestin 介导信号的意义，表达 OXTR 的 HEK-293 细胞在接受催产素处理后，在细胞迁移测定中显示出β-arrestin 依赖性增殖。总之，β-arrestin 是一种多功能支架蛋白，可介导 OXTR 的脱敏，导致子宫收缩力下降，以及催产素刺激后的 MAPK 生长信号。开发可防止受体脱敏的独特 OXTR 配体可能是治疗由于长时间催产素治疗而导致的不良临床事件的新方法。
