The TRPM4 p.I376T variant did not alter electrical activity in young murine hearts but significantly decreased the highly glycosylated fraction of the TRPM4 protein.
Does the TRPM4 p.I376T variant alter cardiac electrophysiology or TRPM4 protein expression in a murine model?
The TRPM4 p.I376T variant reduces highly glycosylated TRPM4 protein expression in the murine heart but does not alter baseline electrical activity at young ages.
TRPM4 is a calcium-activated, voltage-modulated, non-selective cation channel expressed in various tissues, including the heart. In 2016, we reported on a large French family with progressive heart block type I carrying the variant TRPM4 p.I376T. In the present study, the aim was to investigate the consequence of the channel variant TRPM4 p.I376T in cardiac physiology in a newly generated Trpm4 knock-in mouse line. Male and female Trpm4 knock-in (Trpm4I376T/I376T) and wild-type mice of different young ages (12, 18, 24 and 36 weeks old) were phenotyped using surface ECGs. Western blots were performed to quantify TRPM4 protein surface expression in cardiac tissue. Finally, patch-clamp experiments were conducted to quantify the 'TRPM4 current' from freshly isolated ventricular cardiomyocytes. Assessment of cardiac electrophysiology using surface ECGs indicated no significant differences between the two genotypes at any age. Western blot analyses revealed a significant decrease in the highly glycosylated fraction of the TRPM4 protein in Trpm4I376T/I376T hearts compared with wild-type tissues. However, this alteration did not influence the 'TRPM4 current' when comparing Trpm4I376T/I376T and wild-type cardiomyocytes. These results indicate that the TRPM4 variant, TRPM4 p.I376T, does not alter electrical activity in the murine heart at young ages but decreases the amount of highly glycosylated TRPM4 protein expressed in the heart via an unknown mechanism.
Guichard et al. (Wed,) conducted a other in Progressive heart block type I (TRPM4 p.I376T variant). Trpm4 knock-in (Trpm4I376T/I376T) vs. Wild-type mice was evaluated on Cardiac electrophysiology (surface ECGs), TRPM4 protein surface expression, and TRPM4 current. The TRPM4 p.I376T variant did not alter electrical activity in young murine hearts but significantly decreased the highly glycosylated fraction of the TRPM4 protein.