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Cardiotoxicity and the Chinese Thunder God Vine

A large number of drugs and drug candidates cause cardiotoxicity by reducing potassium channel conductance. This can occur in two ways: the compounds can either directly block ionic flow, or they can reduce potassium channel density. Although drug effects on ionic flow can easily be measured by established techniques such as electrophysiological methods, changes in channel density are not as readily assayed, presenting a problem for researchers who want to understand the mechanisms by which these compounds exert inhibition.

Celastrol and several structurally similar compounds were screened for cardiotoxicity.

Now, Haiyan Sun and colleagues have solved this problem using the functional recovery after chemobleaching (FRAC) assay, which measures the rate of protein trafficking with effective throughput. The researchers screened a compound library of 2000 chemicals for potential perturbation of cardiac potassium channel trafficking and found that a significant number of inhibitory compounds affected channel expression. Sun et al. further examined one of the identified inhibitors, celastrol, also known as the Chinese Thunder God vine, which is under investigation for its neuroprotective effects. They found that the compound both reduces channel density on the cell surface and acutely blocks ion conduction, presenting an immediate safety alert for this drug. This study is a technological tour de force that will change the development of current therapeutic approaches while also contributing to our understanding of fundamental biological mechanisms of the regulation of membrane excitability.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 5877–5884

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