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

ABSTRACT: 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 ?-arrestin. In addition to its desensitizing function, ?-arrestins have recently been shown to simultaneously activate downstream signaling. We tested whether oxytocin stimulation promotes ?-arrestin-mediated OXTR desensitization in vivo and activates ?-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 ?-arrestin-1 and ?-arrestin-2 knockout mice showed no desensitization. Utilizing siRNA knockdown of ?-arrestin-1 and ?-arrestin-2 in HEK-293 cells expressing the OXTR, we demonstrated oxytocin-mediated MAPK signaling that was dependent on ?-arrestin-1 and ?-arrestin-2. Wild-type and ?-arrestin-1 and ?-arrestin-2 knockout mice receiving intravenous oxytocin also demonstrated oxytocin-mediated MAPK signaling that was dependent on ?-arrestin-1 and ?-arrestin-2. Finally, to test the significance of ?-arrestin-mediated signaling from the OXTR, HEK-293 cells expressing the OXTR showed ?-arrestin-dependent proliferation in a cell migration assay following oxytocin treatment. In conclusion, ?-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.

SUBMITTER: Grotegut CA

PROVIDER: S-EPMC3064008 | biostudies-other | 2011 Mar

REPOSITORIES: biostudies-other

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

Grotegut Chad A CA Feng Liping L Mao Lan L Heine R Phillips RP Murtha Amy P AP Rockman Howard A HA

American journal of physiology. Endocrinology and metabolism 20101207 3

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 ...[more]

PMID: 21139074

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Project description:BACKGROUND:?2-adrenergic receptors (?2ARs) are the target of catecholamines and play fundamental roles in cardiovascular, pulmonary, and skeletal muscle physiology. An important action of ?2AR stimulation on skeletal muscle is anabolic growth, which has led to the use of agonists such as clenbuterol by athletes to enhance muscle performance. While previous work has demonstrated that ?2ARs can engage distinct signaling and functional cascades mediated by either G proteins or the multifunctional adaptor protein, ?-arrestin, the precise role of ?-arrestin in skeletal muscle physiology is not known. Here, we tested the hypothesis that agonist activation of the ?2AR by clenbuterol would engage ?-arrestin as a key transducer of anabolic skeletal muscle growth. METHODS:The contractile force of isolated extensor digitorum longus muscle (EDL) and calcium signaling in isolated flexor digitorum brevis (FDB) fibers were examined from the wild-type (WT) and ?-arrestin 1 knockout mice (?arr1KO) followed by chronic administration of clenbuterol (1?mg/kg/d). Hypertrophic responses including fiber composition and fiber size were examined by immunohistochemical imaging. We performed a targeted phosphoproteomic analysis on clenbuterol stimulated primary cultured myoblasts from WT and ?arr1KO mice. Statistical significance was determined by using a two-way analysis with Sidak's or Tukey's multiple comparison test and the Student's t test. RESULTS:Chronic administration of clenbuterol to WT mice enhanced the contractile force of EDL muscle and calcium signaling in isolated FDB fibers. In contrast, when administered to ?arr1KO mice, the effect of clenbuterol on contractile force and calcium influx was blunted. While clenbuterol-induced hypertrophic responses were observed in WT mice, this response was abrogated in mice lacking ?-arrestin 1. In primary cultured myoblasts, clenbuterol-stimulated phosphorylation of multiple pro-hypertrophy proteins required the presence of ?-arrestin 1. CONCLUSIONS:We have identified a previously unappreciated role for ?-arrestin 1 in mediating ?2AR-stimulated skeletal muscle growth and strength. We propose these findings could have important implications in the design of future pharmacologic agents aimed at reversing pathological conditions associated with skeletal muscle wasting.

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

Publications

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

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