title: Human TRPV5 and TRPV6: key players in cadmium and zinc toxicity.
abstract: TRPV5 and TRPV6 are two major calcium transport pathways in the human body maintaining calcium homeostasis. TRPV5 is mainly expressed in the distal convoluted and connecting tubule where it is the major, regulated pathway for calcium reabsorption. TRPV6 serves as an important calcium entry pathway in the duodenum and the placenta. Previously, we showed that human TRPV6 (hTRPV6) transports several heavy metals. In this study we tested whether human TRPV5 (hTRPV5) also transports cadmium and zinc, and whether hTRPV5 together with hTRPV6 are involved in cadmium and zinc toxicity. The hTRPV5 mRNA and protein were expressed in HEK293 cells transiently transfected with pTagRFP-C1-hTRPV5. The overexpression of the hTRPV5 protein at the plasma membrane was revealed by cell surface biotinylation and immunofluorescence techniques. We observed that both cadmium and zinc permeate hTRPV5 in ion imaging experiments using Fura-2 or Newport Green DCF. Our results were further confirmed using whole-cell patch clamp technique. Transient overexpression of hTRPV5 or hTRPV6 sensitized cells to cadmium and zinc. Toxicity curves of cadmium and zinc were also shifted in hTRPV6 expressing HEK293 cells clones. Our results suggest that TRPV5 and TRPV6 are crucial gates controlling cadmium and zinc levels in the human body especially under low calcium dietary conditions, when these channels are maximally upregulated.
authors: Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland; Swiss National Centre of Competence in Research, NCCR TransCure, University of Bern, Switzerland. Electronic address: gergely.kovacs@ibmm.unibe.ch.
authors: Gergely
authors: G
authors: Kovacs
authors: Nicolas
authors: N
authors: Montalbetti
authors: Marie-Christine
authors: MC
authors: Franz
authors: Stefanie
authors: S
authors: Graeter
authors: Alexandre
authors: A
authors: Simonin
authors: Matthias A
authors: MA
authors: Hediger
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D015153:Blotting, Western; D002104:Cadmium / Q000633:toxicity*; D015220:Calcium Channels / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014982:Xenopus laevis; D015032:Zinc / Q000633:toxicity*
chemical_list: D015220:Calcium Channels; D050916:TRPV Cation Channels; C492239:TRPV5 protein, human; C422827:TRPV6 protein, human; D002104:Cadmium; D015032:Zinc
keywords: Cadmium; TRPV5; TRPV6; Zinc