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Kouri K, Duchen MR, Lemmens-Gruber R.
Chem Res Toxicol. 2005 Nov;18(11):1661-8.
Effects of beauvericin on the metabolic state and ionic homeostasis of
ventricular myocytes of the guinea pig.
Department of Pharmacology and Toxicology, University of Vienna,
Althanstrasse 14, 1090 Vienna, Austria.
katerina.kouri@univie.ac.at
Beauvericin, a cyclic hexadepsipeptide with antibiotic properties, has been
shown to reduce contraction force and to affect action potential parameters of
guinea pig papillary muscles. Its potential to form cation-selective channels in
mammalian membranes has been demonstrated. Patch clamp and fluorescence imaging
techniques were used to investigate its effects in enzymatically isolated
ventricular myocytes. Application of 10 microM beauvericin caused a large
[Ca2+]i increase in Fura 2AM-loaded cardiomyocytes leading to cell shortening.
The effect could be partially inhibited by ryanodine pretreatment and was
largely dependent on external Ca2+ and blocked by 5 mM Ni2+. Beauvericin
initiated a progressive increase in [Mg2+]i, the time course of which developed
similarly upon increasing the external chemical gradient of Mg2+ 10-fold, to
produce an ionophoric challenge. Monitoring of pH(i) with BCECF showed that
beauvericin caused cytosolic acidification. Confocal microscopy revealed
mitochondrial depolarization in TMRM-loaded cardiomyocytes, which resembled the
effect of classical mitochondrial uncouplers. However, the NADH autofluorescence
signal followed a biphasic pattern, in contrast to the NADH response to the
uncouplers FCCP and the K+-ionophore valinomycin. These results suggest that
beauvericin, possibly via its ionophoric properties, acts as an atypical
mitochondrial uncoupler, greatly disturbs the physiological ionic balance and
pH, challenges cellular metabolism, and causes ATP depletion.
PMID: 16300374
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