Heavy metal cations permeate the TRPV6 epithelial cation channel

Abstract

TRPV6 belongs to the vanilloid family of the transient receptor potential channel (TRP) superfamily. This highly Ca2+-selective channel is expressed in the duodenum and the placenta, where it is responsible for Ca2+ absorption in the body and fetus. Previous observations have suggested that TRPV6 is not only permeable to Ca2+ but also to other divalent cations in epithelial tissues. In this study, we tested whether TRPV6 is indeed also permeable to cations such as Zn2+ and Cd2+. We found that the basal intracellular calcium concentration was higher in HEK293 cells transfected with hTRPV6 than in non-transfected cells, and that the difference almost disappeared in nominally Ca2+-free solution. Live cell imaging experiments with Fura-2 and NewPort Green DCF showed that overexpression of human TRPV6 increased the permeability to Ca2+, Ba2+, Sr2+, Mn2+, Zn2+, Cd2+, and interestingly also to La3+ and Gd3+. These results were confirmed using the patch clamp technique. Furthermore, 45Ca2+ uptake experiments showed that Cd2+, La3+ and Gd3+are efficient inhibitors of TRPV6-mediated Ca2+ influx at higher micromolar concentrations. Our results suggest that TRPV6 is not only involved in Ca2+ transport but also in the transport of other divalent cations, including heavy metal ions, which may have toxicological implications.