TY - JOUR
T1 - Membrane hyperpolarization drives cation influx and fungicidal activity of amiodarone
AU - Maresova, Lydie
AU - Muend, Sabina
AU - Zhang, Yong Qiang
AU - Sychrova, Hana
AU - Rao, Rajini
PY - 2009/1/30
Y1 - 2009/1/30
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M806693200
DO - 10.1074/jbc.M806693200
M3 - Article
C2 - 19054772
AN - SCOPUS:59149090186
SN - 0021-9258
VL - 284
SP - 2795
EP - 2802
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 5
ER -