An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart

Abstract

Voltage-gated sodium channels composed of pore-forming ␣ and auxiliary ␤ subunits are responsible for the rising phase of the action potential in cardiac muscle, but the functional roles of distinct sodium channel subtypes have not been clearly defined. Immunocytochemical studies show that the principal cardiac poreforming ␣ subunit isoform Nav1.5 is preferentially localized in intercalated disks, whereas the brain ␣ subunit isoforms Nav1.1, Nav1.3, and Nav1.6 are localized in the transverse tubules. Sodium currents due to the highly tetrodotoxin (TTX)-sensitive brain isoforms in the transverse tubules are small and are detectable only after activation with ␤ scorpion toxin. Nevertheless, they play an important role in coupling depolarization of the cell surface membrane to contraction, because low TTX concentrations reduce left ventricular function. Our results suggest that the principal cardiac isoform in the intercalated disks is primarily responsible for action potential conduction between cells and reveal an unexpected role for brain sodium channel isoforms in the transverse tubules in coupling electrical excitation to contraction in cardiac muscle.

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

“…Prominent clustering of Na v 1.5 was detected at intercalated disks as well as at the cell surface (Fig. 6C, 6D), consistent with previous observations [20,21,29,30]. No changes in Na v 1.5 localization were observed in spite of increased protein expression (Fig.…”

“…6A, 6B) and Na v 1.6 (Fig. 6E, 6F) were detected at Z-lines/ttubules, consistent with previous reports [20,29]. Prominent clustering of Na v 1.5 was detected at intercalated disks as well as at the cell surface (Fig.…”

“…3C). It has been shown previously that the proportion of TTX-S I Na in mouse ventricular myocytes is very small and detectable only after activation with β-scorpion toxin [20], likely explaining our inability to reliably measure these currents.…”

“…Multiple TTX-S sodium channels are expressed in heart [20,29,47]. 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].…”

“…Solutions were prepared as described [20], including 5 mM extracellular NaCl adjusted to pH 7.4 with CsOH. Series resistance was compensated 40-65% and leak subtraction performed by application of a standard P/4 protocol.…”