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

Dec 9, 2010American journal of physiology. Endocrinology and metabolism

β-Arrestin helps oxytocin signals control uterine contractions and cell movement

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Abstract

Prolonged oxytocin exposure may lead to dysfunctional labor and increased cesarean delivery risk due to oxytocin receptor desensitization.

Desensitization of the oxytocin receptor (OXTR) is linked to diminished uterine contractility after repeated oxytocin exposure.
Mice lacking β-arrestin-1 and β-arrestin-2 did not exhibit OXTR desensitization, suggesting these proteins play a key role.
Oxytocin stimulation activates β-arrestin-mediated signaling that promotes mitogen-activated protein kinase (MAPK) growth signaling.
β-arrestin functions as a scaffold that mediates both OXTR desensitization and MAPK signaling in response to oxytocin.
The findings indicate that developing specific OXTR ligands to prevent receptor desensitization could address complications from prolonged oxytocin therapy.

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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.

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

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