TRPV6 channel function is involved in endometrial epithelial cell Ca²⁺ signaling and female mouse fecundity

The Ca²⁺-selective transient receptor potential vanilloid 6 (TRPV6) channel plays a fundamental role in the female and male murine reproductive system. We have previously shown that TRPV6 is essential for male fertility, and necessary for a proper placental Ca²⁺ transport, embryonic bone development and calcification, as well as for extracellular matrix formation in the placental labyrinth. Here, we show that lack of functional TRPV6 results in impaired fecundity in female mice with increased latency to first pregnancy, longer interpregnancy intervals and fewer and smaller litters. In mouse endometrium the TRPV6 protein is expressed in epithelial cells (MEECs). Using patch clamp recording and Ca²⁺ imaging, we show TRPV6-dependent whole-cell currents and that TRPV6 contributes to cytoplasmic Ca²⁺ signaling in MEECs. MEECs lacking functional TRPV6 Ca²⁺ channels reveal a significantly reduced frequency of spontaneous cytosolic Ca²⁺ oscillations, shown in isolated cells and in situ in whole mount uterus preparations. Our results reveal a previously unknown physiological role for TRPV6 in the regulation of endometrial Ca²⁺ homeostasis and its impact on female fecundity in mice, providing a molecular and cellular framework for further investigation of reproductive disorders, such as those associated with defective Ca²⁺ regulation in women.