TRPM4 contribution in mouse uterine contractions

In brief Inappropriate uterine contractions are a matter of concern during pregnancy or menses. We identified the transient receptor potential melastatin 4 (TRPM4) ion channel as a new actor in mouse uterine contractions highlighting this protein as a potential pharmacological target for a better control of myometrial activity.Control of uterine contractions is of interest in the context of inappropriate myometrial activity during pregnancy and at time of delivery, but it is also a matter for menstrual pain. While several molecular determinants of myometrial contractions have been described, the complete distribution of roles to the various actors is far from understood. A key phenomenon is a variation in cytoplasmic Ca2+ which leads to the activation of calmodulin in smooth muscle and also in the phosphorylation of myosin allowing contraction. The Ca2+ - TRPM4 channel which is known to modulate Ca2+- fluxes in several cell types was shown to participate in vascular as well as detrusor muscle contraction. We thus designed a study to determine whether it also participates in myometrial contraction. Uterine rings were isolated from Trpm4(+/+) and Trpm4(-/-) non-pregnant adult mice and contractions were recorded using an isometric force transducer. In basal conditions, spontaneous contractions were similar in both groups. Application of 9-phenanthrol, a pharmacological TRPM4 inhibitor, dose-dependently reduced contraction parameters in Trpm4(+/+) rings with an IC50 around 2.10(-6) mol/L. The effect of 9-phenanthrol was significantly reduced in Trpm4(-/-) rings. The effect of oxytocin was tested and was found to be stronger in Trpm4(+/+) rings compared to Trpm4(-/-). Under a constant stimulation by oxytocin, 9-phenanthrol still reduced contraction parameters in Trpm4(+/+) rings with a smaller effect on Trpm4(-/-). Altogether it indicates that TRPM4 participates in uterine contractions in mice and may thus be evaluated as a new target to control such contractions.

Automated summary

Inappropriate uterine contractions during pregnancy or menses are a concern. The TRPM4 ion channel has been identified as a potential pharmacological target for better control of myometrial activity in mice.