Depolarization of the myometrial smooth muscle cell (MSMC) resting membrane potential is necessary for the transition of the uterus from a quiescent state to a contractile state. The molecular mechanisms involved in this transition are not completely understood. Here, we report a novel coupled system between the Na+-activated K+ channel (SLO2.1) and the non-selective Na+ leak channel (NALCN) which determines the MSMC membrane potential. We show that SLO2.1 currents are activated by an inward Na+ leak current carried by the NALCN channel leading to MSMC hyperpolarization. These results show an unanticipated role for the Na+ leak currents in activating a negative feedback system countering the excitable effects of Na+ currents. This is a novel role for the NALCN channel in which Na+ acts as an intracellular signaling molecule. In fact, we report here that the net effect of Na+ entry through NALCN channels is a hyperpolarization of the MSMCs plasma membrane because of the activation of SLO2.1 K channel. Importantly, we also report that a decrease in NALCN/SLO2.1 activity triggers both Ca2+ entries through VDCCs, promoting myometrial contraction. Consistently, with a functional coupling, our data show that NALCN and SLO2.1 are in proximity to one another in human MSMCs. We propose that the spatial arrangement of SLO2.1 and NALCN permits these channels to functionally interact in order to regulate human MSMC membrane potential and cell excitability to modulate uterine contractile activity.

中文翻译：

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新型钠信号复合物调节子宫活动

子宫肌层平滑肌细胞（MSMC）静息膜电位的去极化对于子宫从静止状态到收缩状态的转变是必需的。尚未完全了解此转变涉及的分子机制。在这里，我们报告了一种新颖的耦合系统，该系统在Na +激活的K +通道（SLO2.1）和非选择性Na +泄漏通道（NALCN）之间，决定了MSMC膜的潜力。我们显示SLO2.1电流由NALCN通道携带的向内Na +泄漏电流激活，从而导致MSMC超极化。这些结果表明，Na +泄漏电流在激活负反馈系统中抵消了Na +电流的兴奋作用，具有意想不到的作用。这对于其中Na +充当细胞内信号传导分子的NALCN通道具有新的作用。事实上，我们在此报告，由于SLO2.1 K通道的激活，Na +通过NALCN通道进入的净效应是MSMCs质膜的超极化。重要的是，我们还报告了NALCN / SLO2.1活性的降低会触发VDCCs引起的Ca2 +进入，从而促进子宫肌层收缩。一致地，通过功能耦合，我们的数据表明，NALCN和SLO2.1在人类MSMC中彼此接近。我们建议，SLO2.1和NALCN的空间排列允许这些通道在功能上相互作用，以调节人MSMC膜的潜力和细胞兴奋性，以调节子宫的收缩活性。我们还报告说，NALCN / SLO2.1活性的降低会通过VDCC触发Ca2 +的进入，从而促进子宫肌层收缩。一致地，通过功能耦合，我们的数据表明，NALCN和SLO2.1在人类MSMC中彼此接近。我们建议，SLO2.1和NALCN的空间排列允许这些通道在功能上相互作用，以调节人MSMC膜的潜力和细胞兴奋性，以调节子宫的收缩活性。我们还报告说，NALCN / SLO2.1活性的降低会通过VDCC触发Ca2 +的进入，从而促进子宫肌层收缩。一致地，通过功能耦合，我们的数据表明，NALCN和SLO2.1在人类MSMC中彼此接近。我们建议，SLO2.1和NALCN的空间排列允许这些通道在功能上相互作用，以调节人MSMC膜的潜力和细胞兴奋性，以调节子宫的收缩活性。