title: TMC8 (EVER2) attenuates intracellular signaling by Zn2+ and Ca2+ and suppresses activation of Cl- currents.
abstract: Eight paralogue members form the family of transmembrane channel-like (TMC) proteins that share considerable sequence homology to anoctamin 1 (Ano1, TMEM16A). Ano1 is a Ca(2+) activated Cl(-) channel that is related to head and neck cancer, often caused by human papilloma virus (HPV) infection. Mutations in TMC 6 and 8 (EVER1, EVER2) cause epidermodysplasia verruciformis. This rare skin disease is characterized by abnormal susceptibility to HPV infection and cancer. We found that in contrast to Ano1 the common paralogues TMC4-TMC8 did not produce Ca(2+) activated Cl(-) currents when expressed in HEK293 cells. On the contrary, TMC8 was found to be localized in the endoplasmic reticulum (ER), where it inhibited receptor mediated Ca(2+) release, activation of Ano1 and volume regulated LRRC8-related Cl(-) currents. Zn(2+) is co-released from the ER together with Ca(2+) and thereby further augments Ca(2+) store release. Because TMC8 is required to lower cytosolic Zn(2+) concentrations by the Zn(2+) transporter ZnT-1, we hypothesize that HPV infections and cancer caused by mutations in TMC8 are related to upregulated Zn(2+)/Ca(2+) signaling and activation of Ano1.
authors.affiliation: Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Lalida
authors.initials: L
authors.lastname: Sirianant
authors.affiliation: Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Jiraporn
authors.initials: J
authors.lastname: Ousingsawat
authors.affiliation: Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schreiber
authors.affiliation: Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany. Electronic address: karl.kunzelmann@ur.de.
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000075369:Anoctamin-1; D002118:Calcium / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D004553:Electric Conductivity; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D015032:Zinc / Q000494:pharmacology*
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D018118:Chloride Channels; D002712:Chlorides; D007476:Ionophores; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C470315:TMC8 protein, human; D015759:Ionomycin; D000255:Adenosine Triphosphate; D015032:Zinc; D002118:Calcium
keywords: Anoctamin 1; EVER2; LRRC8A; TMC8; Transmembrane channel-like protein; Zn(2+) signaling