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Issue 3, 2017
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Zinc transport and the inhibition of the L-type calcium channel are two separable functions of ZnT-1

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Abstract

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.

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

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Publication details

The article was received on 15 Dec 2016, accepted on 04 Jan 2017 and first published on 04 Jan 2017


Article type: Paper
DOI: 10.1039/C6MT00296J
Citation: Metallomics, 2017,9, 228-238
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    Zinc transport and the inhibition of the L-type calcium channel are two separable functions of ZnT-1

    E. Shusterman, O. Beharier, S. Levy, R. Zarivach, Y. Etzion, C. R. Campbell, I. Lee, A. Dinudom, D. I. Cook, A. Peretz, A. Katz, D. Gitler and A. Moran, Metallomics, 2017, 9, 228
    DOI: 10.1039/C6MT00296J

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