Requirement of neuronal- and cardiac-type sodium channels for murine sinoatrial node pacemaking (original) (raw)

2004, The Journal of Physiology

The majority of Na + channels in the heart are composed of the tetrodotoxin (TTX)-resistant (K D , 2-6 µM) Na v 1.5 isoform; however, recently it has been shown that TTX-sensitive (K D , 1-10 nM) neuronal Na + channel isoforms (Na v 1.1, Na v 1.3 and Na v 1.6) are also present and functionally important in the myocytes of the ventricles and the sinoatrial (SA) node. In the present study, in mouse SA node pacemaker cells, we investigated Na + currents under physiological conditions and the expression of cardiac and neuronal Na + channel isoforms. We identified two distinct Na + current components, TTX resistant and TTX sensitive. At 37 • C, TTX-resistant i Na and TTX-sensitive i Na started to activate at ∼ −70 and ∼ −60 mV, and peaked at −30 and −10 mV, with a current density of 22 ± 3 and 18 ± 1 pA pF −1 , respectively. TTX-sensitive i Na inactivated at more positive potentials as compared to TTX-resistant i Na . Using action potential clamp, TTX-sensitive i Na was observed to activate late during the pacemaker potential. Using immunocytochemistry and confocal microscopy, different distributions of the TTX-resistant cardiac isoform, Na v 1.5, and the TTX-sensitive neuronal isoform, Na v 1.1, were observed: Na v 1.5 was absent from the centre of the SA node, but present in the periphery of the SA node, whereas Na v 1.1 was present throughout the SA node. Nanomolar concentrations (10 or 100 nM) of TTX, which block TTX-sensitive i Na , slowed pacemaking in both intact SA node preparations and isolated SA node cells without a significant effect on SA node conduction. In contrast, micromolar concentrations (1-30 µM) of TTX, which block TTX-resistant i Na as well as TTX-sensitive i Na , slowed both pacemaking and SA node conduction. It is concluded that two Na + channel isoforms are important for the functioning of the SA node: neuronal (putative Na v 1.1) and cardiac Na v 1.5 isoforms are involved in pacemaking, although the cardiac Na v 1.5 isoform alone is involved in the propagation of the action potential from the SA node to the surrounding atrial muscle.