Requirement of neuronal‐ and cardiac‐type sodium channels for murine sinoatrial node pacemaking

Abstract

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.

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

“…Several lines of evidence have shown that TTX-S channels are localized at t-tubules in ventricular myocytes [21,29] and in sinoatrial node [47,48], although the physiological role of these channels is not well understood [20,49]. We propose that at least a portion of the increased I NaP observed in Scn1b null myocytes may be attributable to one or more TTX-S channels in addition to effects on TTX-R Na v 1.5.…”

Remodeling of the Cardiac Pacemaker L-Type Calcium Current and Its β-Adrenergic Responsiveness in Hypertension After Neuronal NO Synthase Gene Transfer

“…Individual SAN cells were isolated from right atria of the SHR and WKY based on methods described previously 36 with some modifications (see Methods in the online supplement).…”

Contribution of Nav1.1 to cellular synchronization and automaticity in spontaneous beating cultured neonatal rat ventricular cells

“…Low concentration of TTX, 100-200 nM, inhibited Na v 1.1, while full inhibition of Na v 1.5 required more than 20-30 µM TTX (Antoni et al 1988;Maier et al 2003;Lei et al 2004). These pharmacological treatments could easily separate Na v 1.1 from Na v 1.5.…”

“…Several Na + channel isoforms, with Na v 1.5 channel being a main, were confirmed in the cardiac tissue (Haufe et al 2005). However, Na v 1.1, Na v 1.3 and Na v 1.6 that preferentially expressed in neurons are also detected (Maier et al 2003;Lei et al 2004). Previous studies have demonstrated that Na v 1.5 is involved in action potential propagation, but both Na v 1.1 and Na v 1.5 contribute to the pacemaking in SAN (Haufe et al 2005).…”