Membrane hyperpolarization drives cation influx and fungicidal activity of amiodarone

Lydie Maresova, Sabina Muend, Yong Qiang Zhang, Hana Sychrova, Rajini Rao

Research output: Contribution to journalArticlepeer-review

Abstract

Cationic amphipathic drugs, such as amiodarone, interact preferentially with lipid membranes to exert their biological effect. In the yeast Saccharomyces cerevisiae, toxic levels of amiodarone trigger a rapid influx of Ca2+ that can overwhelm cellular homeostasis and lead to cell death. To better understand the mechanistic basis of antifungal activity, we assessed the effect of the drug on membrane potential. We show that low concentrations of amiodarone (0.1-2 μM) elicit an immediate, dose-dependent hyperpolarization of the membrane. At higher doses (> 3 μM), hyperpolarization is transient and is followed by depolarization, coincident with influx of Ca2+ and H+ and loss in cell viability. Proton and alkali metal cation transporters play reciprocal roles in membrane polarization, depending on the availability of glucose. Diminishment of membrane potential by glucose removal or addition of salts or in pma1, tok1Δ, ena1-4Δ, or nha1Δ mutants protected against drug toxicity, suggesting that initial hyperpolarization was important in the mechanism of antifungal activity. Furthermore, we show that the link between membrane hyperpolarization and drug toxicity is pH-dependent. We propose the existence of pH- and hyperpolarization-activated Ca2+ channels in yeast, similar to those described in plant root hair and pollen tubes that are critical for cell elongation and growth. Our findings illustrate how membrane-active compounds can be effective microbicidals and may pave the way to developing membrane-selective agents.

Original languageEnglish (US)
Pages (from-to)2795-2802
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number5
DOIs
StatePublished - Jan 30 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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