Related Experiment Video
Updated: Jul 7, 2026
Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
Published on: July 3, 2013
Fungicidal activity of amiodarone is tightly coupled to calcium influx
1Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Abstract:
The antiarrhythmic drug amiodarone has microbicidal activity against fungi, bacteria and protozoa. In Saccharomyces cerevisiae, amiodarone triggers an immediate burst of cytosolic Ca2+, followed by cell death markers. Ca2+ transients are a common response to many forms of environmental insults and toxic compounds, including osmotic and pH shock, endoplasmic reticulum stress, and high levels of mating pheromone. Downstream signaling events involving calmodulin, calcineurin and the transcription factor Crz1 are critical in mediating cell survival in response to stress. In this study we asked whether amiodarone induced Ca2+ influx was beneficial, toxic or a bystander effect unrelated to the fungicidal effect of the drug. We show that downregulation of Ca2+ channel activity in stationary phase cells correlates with increased resistance to amiodarone. In actively growing cells, extracellular Ca2+ modulated the size and shape of the Ca2+ transient and directly influenced amiodarone toxicity. Paradoxically, protection was achieved both by removal of external Ca2+ or by adding high levels of CaCl2 (10 mM) to block the drug induced Ca2+ burst. Our results support a model in which the fungicidal activity of amiodarone is mediated by Ca2+ stress, and highlight the pathway of Ca2+ mediated cell death as a promising target for antifungal drug development.
Insights
The antiarrhythmic drug amiodarone kills microbes by inducing calcium (Ca2+) stress in cells. Blocking this Ca2+ influx can protect cells, suggesting a new antifungal drug target.
Area of Science:
- Microbiology
- Cell Biology
- Pharmacology
Background:
- Amiodarone, an antiarrhythmic drug, exhibits microbicidal activity against fungi, bacteria, and protozoa.
- In yeast (Saccharomyces cerevisiae), amiodarone induces a rapid increase in cytosolic calcium (Ca2+), leading to cell death.
- Calcium transients are cellular responses to various environmental stresses, involving signaling pathways like calmodulin, calcineurin, and Crz1.
Purpose of the Study:
- To investigate whether the amiodarone-induced Ca2+ influx is a cause, consequence, or unrelated bystander effect of its fungicidal activity.
- To determine the role of extracellular Ca2+ in amiodarone's toxicity and cellular resistance.
Main Methods:
- Assessing amiodarone resistance in yeast with varying Ca2+ channel activity.
- Manipulating extracellular Ca2+ concentrations in actively growing yeast cells.
- Observing the effects of Ca2+ modulation on amiodarone-induced Ca2+ transients and cell viability.
Main Results:
- Downregulation of Ca2+ channel activity correlated with increased resistance to amiodarone in stationary phase cells.
- Extracellular Ca2+ levels modulated the Ca2+ transient and directly impacted amiodarone toxicity in growing cells.
- Both removal of external Ca2+ and addition of high CaCl2 (10 mM) conferred protection by blocking the Ca2+ burst.
Conclusions:
- Amiodarone's fungicidal effect is mediated by inducing cellular Ca2+ stress.
- The Ca2+ influx pathway is a potential target for developing novel antifungal therapies.
More Related Videos
10:01High-Throughput Optical Controlling and Recording Calcium Signal in iPSC-Derived Cardiomyocytes for Toxicity Testing and Phenotypic Drug Screening
Published on: March 31, 2022
07:42Contractions of Human-iPSC-derived Cardiomyocyte Syncytia Measured with a Ca-sensitive Fluorescent Dye in Temperature-controlled 384-well Plates
Published on: October 18, 2018
Related Concept Videos
01:12Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers
01:20Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers
Verapamil, a calcium channel blocker, inhibits calcium movement across myocardial cell membranes and vascular smooth muscle. This results in the dilation of coronary and...
01:18Antihypertensive Drugs: Action of Calcium Channel Blockers
01:22Antiarrhythmic Drugs: Class I Agents as Sodium Channel Blockers
Class 1A Antiarrhythmic Drugs: These drugs work by moderately blocking sodium channels,...
01:27Feedback Regulation of Calcium Concentration
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
01:25Antianginal Drugs: Calcium Channel Blockers and Ranolazine
CCBs, a diverse class that includes dihydropyridines (nifedipine) and diphenylalkylamines (verapamil and diltiazem), exert their effect by blocking calcium channels in cardiac and smooth muscle cells. This...