TRPV6 [transient receptor potential vanilloid 6] is a calcium ion (Ca²+)-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 Ca²+ 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 Ca²+ absorption through the epididymal epithelium and was associated with reduced sperm viability. Thus, appropriate Ca²+ absorption and a consequent TRPV6-mediated decrease in the extracellular Ca²+ concentration toward the distal segments of the epididymal duct are essential for the acquisition of basic functions and the survival of spermatozoa.

The present findings outline a new signaling cascade in the induction of PAF-induced lung edema, in that stimulation of ASM causes recruitment of TRPC6 channels to caveolae, thus allowing for Ca(2+) influx and subsequent increases in endothelial permeability that are amplified in the absence of endothelial NO synthesis.

Background: The TRPV6D541A pore mutation abrogates epididymal Ca 2ϩ absorption causing hypofertility in mice, raising the possibility of residual TRPV6 D541A channel activity. Results: Trpv6 deletion reduces fertility parameters to the same extent as the D541A pore mutation. Conclusion:The D541A pore mutation leads to complete inactivation of TRPV6 channels in epididymal epithelium. Significance: Targeted mutations in mice help to understand the function of TRPV6 proteins in native systems.

Background:The TRPV6 amino acid sequence is predicted from its cDNA. Results: The TRPV6 protein purified from human tissues has an extended N terminus not present in the predicted protein. Conclusion:Full-length TRPV6 is trafficked to the plasma membrane, and its translation efficiency tightly controls TRPV6-mediated Ca 2ϩ entry. Significance: This study provides mechanistic insights into the function of the full-length TRPV6.

Background: Gating mechanisms of TRPC channels are mostly unknown. Results: Replacing the highly conserved glycine residue within the linker between transmembrane domains 4 and 5 by serine renders TRPC4 and TRPC5 channels constitutively active. Conclusion: TRPC channel opening seems to require similar constraints than the voltage-gated potassium channels. Significance: Novel mechanistic insights into structural requirements of TRPC channel gating are provided.