Zinc transport and the inhibition of the L-type calcium channel are two separable functions of ZnT-1

Eden Shusterman, Ofer Beharier, Shiri Levy, Raz Zarivach, Yoram Etzion, Craig R. Campbell, Il Ha Lee, Anuwat Dinudom, David I. Cook, Asher Peretz, Amos Katz, Daniel Gitler, Arie Moran

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Traditionally, proteins are considered to perform a single role, be it as an enzyme, a channel, a transporter or as a structural scaffold. However, recent studies have described moonlighting proteins that perform distinct and independent functions; for example, TRPM7 is both an ion channel and a kinase. ZnT-1 is a member of the Carrier Diffusion Facilitator family that is expressed throughout the phylogenetic tree from bacteria to humans. Since its cloning in 1995, ZnT-1 is considered a major extruder of Zn2+ based on its capability to protect cells against zinc toxicity. Recently, we reported that ZnT-1 inhibits the L-type calcium channel (LTCC), a major Zn2+ and Ca2+ entry pathway. Here we show that ZnT-1 is a dual-function protein by demonstrating that its abilities to exchange Zn2+/H+ and to inhibit the LTCC are independent of each other and are mediated by different parts of the protein. Specifically, mutations in the membrane-spanning helices that render ZnT-1 unable to transport zinc do not prevent it from inhibiting the LTCC. Moreover, a fragment consisting of the intracellular ZnT-1 C-terminal, which lacks all ion-transfer segments, inhibits the LTCC as efficiently as wild-type ZnT-1. Our data therefore indicates that ZnT-1 performs two structurally independent functions related to zinc homeostasis.

Original languageEnglish
Pages (from-to)228-238
Number of pages11
Issue number3
StatePublished - 1 Mar 2017

ASJC Scopus subject areas

  • General Medicine


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