SLO2.1/NALCN Functional Complex Activity in Mouse Myometrial Smooth Muscle Cells During Pregnancy.

At the end of pregnancy, the uterus transitions from a quiescent to a highly contractile state. This is partly due to the depolarization of the resting membrane potential in uterine (myometrial) smooth muscle cells (MSMCs). In human MSMCs, the membrane potential is regulated by a functional complex between the sodium (Na(+))-activated potassium (K(+)) channel SLO2.1 and the Na(+) leak channel nonselective (NALCN). Na(+) entering through NALCN activates SLO2.1, leading to K(+) efflux, membrane hyperpolarization (cells become more negative inside), and reduced contractility. Decreased SLO2.1/NALCN activity results in reduced K(+) efflux, leading to membrane depolarization, Ca(2+) influx via voltage-dependent calcium channels, and increased MSMC contractility. However, all of these data are from MSMCs isolated from women at term, so the role of the SLO2.1/NALCN complex early in pregnancy was speculative. To address this question here, we examined the role of the SLO2.1/NALCN complex in regulating mouse MSMC membrane potential across pregnancy. We report that Slo2.1 and Nalcn are more highly expressed in MSMCs from nonpregnant and early pregnant mice than in those from late-pregnant mice. Functional studies revealed that SLO2.1 channels mediate a significant portion of the K(+) current in mouse MSMCs, particularly in cells from nonpregnant and early pregnant mice. Activation of SLO2.1 by Na(+) influx through NALCN led to membrane hyperpolarization in MSMCs from early pregnancy but not in MSMCs from later pregnancy. Moreover, the NALCN/SLO2.1 complex regulates intracellular Ca(2+) responses more in MSMCs from nonpregnant and early pregnancy mice than in MSMCs from late pregnancy. Together, these findings reveal that the SLO2.1/NALCN functional complex is conserved between mice and humans and functions throughout pregnancy. This study could open avenues for targeted pharmacological interventions for pregnancy-related complications.