Activation of Vasopressin Receptor 1A by Vasopressin Enhances Myometrial Smooth Muscle Cell Excitability by Inhibiting the Potassium Channel SLO2.1

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Arginine vasopressin (AVP) increases excitability of myometrial smooth muscle cells (MSMCs) through Gαq-coupled AVP receptors. Although excitability requires membrane depolarization, the mechanisms linking AVP receptor activation to membrane depolarization and Ca²⁺ signaling are incompletely understood. Here, we show that AVPR1 is the predominant AVP receptor in primary MSMCs. In Xenopus oocytes, AVP signals through AVPR1 to inhibit SLO2.1-mediated potassium currents, reducing current amplitude to approximately 60% of control currents. Consistent with suppression of a hyperpolarizing conductance, AVP depolarized a myometrial cell line (hTERT-HM) and increased intracellular Ca²⁺ signaling. Analysis of Ca²⁺ dynamics revealed that the initial Ca²⁺ peak was largely preserved under conditions limiting extracellular Ca²⁺ entry, consistent with intracellular store release. Conversely, the oscillatory phase depended on extracellular Ca²⁺ influx and was reduced by SLO2.1 knockdown. Together, these findings support a model in which AVP preferentially signals through AVPR1A to inhibit SLO2.1, depolarize myometrial cells, enhance VDCC-dependent Ca²⁺ entry, and promote excitability, enhancing conditions for uterine contraction.