β-Arrestin mediates oxytocin receptor signaling, which regulates uterine contractility and cellular migration

Grotegut CA, Feng L, Mao L, Heine RP, Murtha AP, Rockman HA. beta-Arrestin mediates oxytocin receptor signaling, which regulates uterine contractility and cellular migration. Am J Physiol Endocrinol Metab 300: E468-E477, 2011. First published December 7, 2010; doi:10.1152/ajpendo.00390.2010.-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 beta-arrestin. In addition to its desensitizing function, beta-arrestins have recently been shown to simultaneously activate downstream signaling. We tested whether oxytocin stimulation promotes beta-arrestin-mediated OXTR desensitization in vivo and activates beta-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 beta-arrestin-1 and beta-arrestin-2 knockout mice showed no desensitization. Utilizing siRNA knockdown of beta-arrestin-1 and beta-arrestin-2 in HEK-293 cells expressing the OXTR, we demonstrated oxytocin-mediated MAPK signaling that was dependent on beta-arrestin-1 and beta-arrestin-2. Wild-type and beta-arrestin-1 and beta-arrestin-2 knockout mice receiving intravenous oxytocin also demonstrated oxytocin-mediated MAPK signaling that was dependent on beta-arrestin-1 and beta-arrestin-2. Finally, to test the significance of beta-arrestin-mediated signaling from the OXTR, HEK-293 cells expressing the OXTR showed beta-arrestin-dependent proliferation in a cell migration assay following oxytocin treatment. In conclusion, beta-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.