Background and Objective: Both atrial fibrillation and ventricular tachyarrhythmias are associated with structural remodeling processes of the myocardium and changes in hemodynamics that translate into alterations in the mechanical strain of cardiomyocytes. Transmembrane proteins of the Tmem120 family have recently been identified as correlates of mechanosensitive ion currents where they are discussed to play a major role in pain perception. However, whether these channels display myocardial expression and play a role in the development of cardiac arrhythmias remains unclear. The aim of this project was to study the expression of Tmem120 channels in the human heart under healthy and diseased conditions and to pharmacologically characterize Tmem120a-mediated currents.

Methods: Expression levels of Tmem120a and Tmem120b were analyzed by TaqMan qPCR in human atrial and ventricular tissue samples obtained from patients with different forms of atrial cardiomyopathy. Further, a model for dual-electrode voltage clamp measurements of Tmem120a channels heterologously expressed in Xenopus laevis oocytes was established and used to characterize the effects of GsMTx4, Gd³⁺, and ruthenium red as well as the antiarrhythmic drugs amiodarone and mexiletine on these channels.

Results: Cardiac mRNA levels of Tmem120 were significantly higher than those of other mechanosensitive channels such as TREK-1, Piezo1, or Piezo2. Whereas Tmem120a exhibited ventricle-accented expression patterns, Tmem120b mRNA expression was found to be almost atrial specific. Interestingly, patients suffering from chronic atrial fibrillation showed significantly decreased atrial Tmem120b mRNA expression levels. Upon heterologous expression in Xenopus laevis oocytes, Tmem120 channels gave rise to macroscopic currents that were inhibited by typical blockers of mechanosensitive currents such as GsMTx4 and Gd³⁺ but not by ruthenium red. Whereas Tmem120 meditated currents were visually insensitive to amiodarone, the class I antiarrhythmic drug mexiletine was found to exhibit concentration-dependent inhibition of Tmem120 currents.

Conclusions: Compartment-specific expression patterns, dysregulation in patients with chronic atrial fibrillation, and interactions with the antiarrhythmic drug mexiletine suggest a cardiac relevance of this channel family and point towards a potential role in the pathophysiology of cardiac arrhythmias.