Zusammenfassung
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 Ca2+ 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 ...
Zusammenfassung
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 Ca2+ 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 Ca2+ 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 Ca2+ release, activation of Ano1 and volume regulated LRRC8-related Cl- currents. Zn2+ is co-released from the ER together with Ca2+ and thereby further augments Ca2+ store release. Because TMC8 is required to lower cytosolic Zn2+ concentrations by the Zn2+ transporter ZnT-1, we hypothesize that HPV infections and cancer caused by mutations in TMC8 are related to upregulated Zn2+/Ca2+ signaling and activation of Ano1. (C) 2014 Elsevier Inc All rights reserved.
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