Exploring the Role of TRPM4 in Calcium Dependent Triggered Activity and Cardiac Arrhythmias.

Cardiac arrhythmias pose a major threat to a patient's health, yet prove to be often difficult to predict, prevent and treat. A key mechanism in the occurrence of arrhythmias is disturbed Ca 2+ homeostasis in cardiac muscle cells. As a Ca 2+ -activated non-selective cation channel, TRPM4 has been linked to Ca 2+ -induced arrhythmias, potentially contributing to translating an increase in intracellular Ca 2+ concentration into membrane depolarisation and an increase in cellular excitability. Indeed, evidence from genetically modified mice, analysis of mutations in human patients and the identification of a TRPM4 blocking compound that can be applied in vivo further underscores this hypothesis. Here, we provide an overview of these data in the context of our current understanding of Ca 2+ -dependent arrhythmias. Abstract figure legend In the context of pathological conditions such as CPVT, ischemia or atrial fibrillation, spontaneous Ca 2+ release events occur. These spontaneous Ca 2+ release events trigger a Ca 2+ -dependent arrhythmogenic transient inward current (I ti ), generating delayed afterdepolarizations (DADs), which is the underlying mechanism for Ca 2+ dependent triggered activity. The major contributor of I ti is NCX, though Ca 2+ -activated Cl - channels (CACC) and Ca 2+ -activated non-selective cation (CAN) channels might also contribute to some extent. However, an important aspect of triggered activity is the excitability of cardiomyocytes, which is determined by a background current, which consists of the late Na + current (I Na,L ), NCX activity in the forward mode and the CAN channel TRPM4. Recent results have shown that meclofenamate inhibits TRPM4, and in this way prevents and suppresses Ca 2+ dependent arrhythmias. This article is protected by copyright. All rights reserved.