Objective: A calcium-activated nonselective cation channel (NSC_Ca) has been recently described in several cardiac preparations. This channel is over-expressed in models of ventricular hypertrophy showing electrophysiological perturbations of heart activity, including occurrence of spontaneous activity. While these perturbations are currently attributed to a modification of the pacemaker I_f current activity, arguments are also in favor of participation of an NSC_Ca. Similarly, the NSC_Ca may be expressed in specialized pacemaker cells, i.e. sino-atrial node (SAN) cells. The aim of the present study was to detect such current in mouse pacemaker cells.

Methods: The inside-out configuration of the patch-clamp technique was used in freshly isolated SAN cells from adult mice. Also, RT-PCR and Western-blotting studies were used to probe for TRPM4 mRNA and protein expression.

Results: In these cells, an NSC_Ca activity was detected. The channel is voltage dependant with a conductance of 20.9±0.5 pS (n=11). It is equally permeable for Na⁺ and K⁺ but does not conduct Ca²⁺. It is activated by rise in intracellular calcium concentrations and blocked by intracellular ATP (0.5 mmol/L). Also, as a new property in cardiac cells, the channel is activated by internal application of phosphatidylinositol 4,5-bisphosphate (10 μM). It is reversibly inhibited by flufenamic acid and glibenclamide. This channel shows the hallmarks of the TRPM4 molecule, a member of the TRP melastatin subfamily. We confirm the expression of this TRP channel on SAN cells by Western blotting and RT-PCR and validate that TRPM4 is glibenclamide sensitive.

Conclusion: TRPM4 is functionally expressed in SAN cells and may be a key player in the generation and/or perturbation of heart rhythm.