Uncoupling cytosolic calcium from membrane voltage by transient receptor potential melastatin 4 channel (TRPM4) modulation: A novel strategy to treat ventricular arrhythmias

The current antiarrhythmic paradigm is mainly centered around modulating membrane voltage. However, abnormal cytosolic calcium (Ca(2+)) signaling, which plays an important role in driving membrane voltage, has not been targeted for therapeutic purposes in arrhythmogenesis. There is clear evidence for bidirectional coupling between membrane voltage and intracellular Ca(2+). Cytosolic Ca(2+) regulates membrane voltage through Ca(2+)-sensitive membrane currents. As a component of Ca(2+)-sensitive currents, Ca(2)(+)-activated nonspecific cationic current through the TRPM4 (transient receptor potential melastatin 4) channel plays a significant role in Ca(2+)-driven changes in membrane electrophysiology. In myopathic and ischemic ventricles, upregulation and/or enhanced activity of this current is associated with the generation of afterdepolarization (both early and delayed), reduction of repolarization reserve, and increased propensity to ventricular arrhythmias. In this review, we describe a novel concept for the management of ventricular arrhythmias in the remodeled ventricle based on mechanistic concepts from experimental studies, by uncoupling the Ca(2+)-induced changes in membrane voltage by inhibition of this TRPM4-mediated current.