Molecular basis for zinc transporter 1 action as an endogenous inhibitor of L-type calcium channels

Shiri Levy, Ofer Beharier, Yoram Etzion, Merav Mor, Liat Buzaglo, Lior Shaltiel, Levi A. Gheber, Joy Kahn, Anthony J. Muslin, Amos Katz, Daniel Gitler, Arie Moran*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

The L-type calcium channel (LTCC) has a variety of physiological roles that are critical for the proper function of many cell types and organs. Recently, a member of the zinc-regulating family of proteins, ZnT-1, was recognized as an endogenous inhibitor of the LTCC, but its mechanism of action has not been elucidated. In the present study, using two-electrode voltage clamp recordings in Xenopus oocytes, we demonstrate that ZnT-1-mediated inhibition of the LTCC critically depends on the presence of the LTCC regulatory a-subunit. Moreover, the ZnT-1-induced inhibition of the LTCC current is also abolished by excess levels of the β-subunit. An interaction between ZnT-1 and the β-subunit, as demonstrated by co-immunoprecipitation and by fluorescence resonance energy transfer, is consistent with this result. Using surface biotinylation and total internal reflection fluorescence microscopy in HEK293 cells, we show a ZnT-1-dependent decrease in the surface expression of the pore-forming α1-subunit of the LTCC. Similarly, a decrease in the surface expression of the α1-subunit is observed following up-regulation of the expression of endogenous ZnT-1 in rapidly paced cultured cardiomyocytes.Weconclude that ZnT-1-mediated inhibition of the LTCC is mediated through a functional interaction of ZnT-1 with the LTCC β-subunit and that it involves a decrease in the trafficking of the LTCC α1-subunit to the surface membrane.

Original languageAmerican English
Pages (from-to)32434-32443
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number47
DOIs
StatePublished - 20 Nov 2009
Externally publishedYes

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