The TRPM4 non-selective cation channel contributes to the mammalian atrial action potential

Abstract

The TRPM4 calcium-activated non-selective monovalent cation channel has been reported in mammalian atrial cardiomyocytes, but its implication in this tissue remains unknown. We used a combination of pharmacological tools and disruption of the Trpm4 gene in mice to investigate the channel implication in atrial action potential (AP). To search for TRPM4 activity, single channel currents were recorded on freshly isolated atrial cardiomyocytes using the patch-clamp technique. To investigate TRPM4 implication in AP, the transmembrane potential was recorded on the multicellular preparation using intracellular microelectrodes after isolating the mouse atrium, under electrical stimulation (rate=5Hz). Isolated atrial cardiomyocytes from the Trpm4(+/+) mouse expressed a typical TRPM4 current while cardiomyocytes from Trpm4(-/-) mouse did not. The Trpm4(+/+) mouse atrium exhibited AP durations at 50, 70 and 90% repolarization of 8.9±0.5ms, 16.0±1.0ms, and 30.2±1.6ms, respectively. The non-selective cation channel inhibitor flufenamic acid (10(-6) and 10(-5)mol·L(-1)) produced a concentration-dependent decrease in AP duration. Similarly, the TRPM4-inhibitor 9-phenanthrol reversibly reduced the duration of AP with an EC50 at 21×10(-6)mol·L(-1), which is similar to that reported for TRPM4 current inhibition in HEK-293 cells. 9-Phenanthrol had no effect on other AP parameters. The effect of 9-phenanthrol is markedly reduced in the mouse ventricle, which displays only weak expression of the channel. Moreover, atria from Trpm4(-/-) mice exhibited an AP that was 20% shorter than that of atria from littermate control mice, and the effect of 9-phenanthrol on AP was abolished in the Trpm4(-/-) mice. Our results showed that TRPM4 is implicated in the waveform of the atrial action potential. It is thus a potential target for pharmacological approaches against atrial arrhythmias.