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Cell Signal. 2014 Dec;26(12):2826-33. doi: 10.1016/j.cellsig.2014.09.001. Epub 2014 Sep 15.

TMC8 (EVER2) attenuates intracellular signaling by Zn2+ and Ca2+ and suppresses activation of Cl- currents.

Author information

1
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
2
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany. Electronic address: karl.kunzelmann@ur.de.

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.

KEYWORDS:

Anoctamin 1; EVER2; LRRC8A; TMC8; Transmembrane channel-like protein; Zn(2+) signaling

PMID:
25220380
DOI:
10.1016/j.cellsig.2014.09.001
[Indexed for MEDLINE]

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