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bioRxiv · 10.1101/2024.05.29.596465

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

Ferreira, J. J.·Kent, L. N.·McCarthy, R.·Butler, A.·Ma, X.·Paramsetty, N.·Amazu, C.·Zhang, A.·Whitter, G. C.·England, S. K.·Santi, C. M.
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Abstract

At the end of pregnancy, the uterus transitions from a quiescent to a highly contractile state. This is partly due to 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 Non-Selective (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, Ca2+ 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 non-pregnant 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 non-pregnant 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 Ca2+ responses more in MSMCs from non-pregnant and early pregnancy mice than in MSMCs from late pregnancy. Together, these findings reveal that the SLO2.1/NALCN functional complex is conserved between mouse and humans and functions throughout pregnancy. This work could open avenues for targeted pharmacological interventions for pregnancy-related complications.

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Ferreira, J. J., Kent, L. N., McCarthy, R., Butler, A., Ma, X., Paramsetty, N., Amazu, C., Zhang, A., Whitter, G. C., England, S. K., Santi, C. M.. 2024-06-02. SLO2.1/NALCN Functional Complex Activity in Mouse Myometrial Smooth Muscle Cells During Pregnancy.. https://doi.org/10.1101/2024.05.29.596465

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