Male Fertility Depends on Ca 2+ Absorption by TRPV6 in Epididymal Epithelia

Production of functional spermatozoa requires regulation of the Ca 2+ concentration in epididymal fluid by TRPV6. Male infertility can result from decreased production of or functional deficits in sperm. Ca 2+ signaling plays a crucial role in sperm function, and, here, Weissgerber et al . uncovered a role for the Ca 2+ -selective TRPV6 channel in regulating Ca 2+ concentration in the lumen of the epididymis as well as sperm motility and survival. Sperm maturation—including the acquisition of motility—occurs in the epididymis, after their exit from the testis. Male transgenic mice bearing an inactive form of TRPV6 showed decreased fertility, and the motility, viability, and in vitro capacity to fertilize eggs of sperm isolated from their caudal epididymides were impaired. TRPV6 was present in epididymal epithelial cells but not in the sperm themselves, and the Ca 2+ concentration in the lumens of the epididymides of transgenic mice was 10 times higher than in wild-type mice. Moreover, sperm exposed to comparable extracellular Ca 2+ concentrations showed an increase in intracellular Ca 2+ concentration. The authors thus conclude that TRPV6 channels function to decrease the Ca 2+ concentration of the intraluminal fluid in the epididymis and propose that the impaired function and survival of sperm in the transgenic mice results from the disturbed microenvironment in the epididymal fluid. TRPV6 [transient receptor potential vanilloid 6] is a calcium ion (Ca 2+ )–selective channel originally identified in the duodenal epithelium and in placenta; replacement of a negatively charged aspartate in the pore-forming region with an uncharged alanine (D541A) renders heterologously expressed TRPV6 channels nonfunctional. We found that male, but not female, mice homozygous for this mutation ( Trpv6 D541A/D541A ) showed severely impaired fertility. The motility and fertilization capacity of sperm were markedly reduced, despite intact spermatogenesis. Trpv6 was expressed in epididymal epithelium where the protein was detected in the apical membrane, whereas it was not expressed in spermatozoa or the germinal epithelium. The Ca 2+ concentration of the fluid in the cauda epididymis of Trpv6 D541A/D541A males was 10 times higher than that of wild-type mice, which was accompanied by a seven- to eightfold decrease in Ca 2+ absorption through the epididymal epithelium and was associated with reduced sperm viability. Thus, appropriate Ca 2+ absorption and a consequent TRPV6-media