ZnT-1 enhances the activity and surface expression of T-type calcium channels through activation of Ras-ERK signaling

Merav Mor, Ofer Beharier, Shiri Levy, Joy Kahn, Shani Dror, Daniel Blumenthal, Levi A. Gheber, Asher Peretz, Amos Katz, Arie Moran, Yoram Etzion

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Zinc transporter-1 (ZnT-1) is a putative zinc transporter that confers cellular resistance from zinc toxicity. In addition, ZnT-1 has important regulatory functions, including inhibition of L-type calcium channels and activation of Raf-1 kinase. Here we studied the effects of ZnT-1 on the expression and function of T-type calcium channels. In Xenopus oocytes expressing voltage-gated calcium channel (CaV) 3.1 or CaV3.2, ZnT-1 enhanced the low-threshold calcium currents (IcaT) to 182 ± 15 and 167.95 ± 9.27% of control, respectively (P < 0.005 for both channels). As expected, ZnT-1 also enhanced ERK phosphorylation. Coexpression of ZnT-1 and nonactive Raf-1 blocked the ZnT-1-mediated ERK phosphorylation and abolished the ZnT-1-induced augmentation of IcaT. In mammalian cells (Chinese hamster ovary), coexpression of CaV3.1 and ZnT-1 increased the IcaT to 166.37 ± 6.37% compared with cells expressing CaV3.1 alone (P < 0.01). Interestingly, surface expression measurements using biotinylation or total internal reflection fluorescence microscopy indIcaTed marked ZnT-1-induced enhancement of CaV3.1 surface expression. The MEK inhibitor PD-98059 abolished the ZnT-1-induced augmentation of surface expression of CaV3.1. In cultured murine cardiomyocytes (HL-1 cells), transient exposure to zinc, leading to enhanced ZnT-1 expression, also enhanced the surface expression of endogenous CaV3.1 channels. Consistently, in these cells, endothelin-1, a potent activator of Ras-ERK signaling, enhanced the surface expression of CaV3.1 channels in a PD-98059-sensitive manner. Our findings indIcaTe that ZnT-1 enhances the activity of CaV3.1 and CaV3.2 through activation of Ras-ERK signaling. The augmentation of CaV3.1 currents by Ras-ERK activation is associated with enhanced trafficking of the channel to the plasma membrane.

Original languageEnglish
Pages (from-to)C192-C203
JournalAmerican Journal of Physiology - Cell Physiology
Volume303
Issue number2
DOIs
StatePublished - 15 Jul 2012

Keywords

  • Extracellular signal-regulated kinase signaling
  • Trafficking

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