Characterization of Sodium Channel α- and β-Subunits in Rat and Mouse Cardiac Myocytes

Abstract

Background-Sodium channels isolated from mammalian brain are composed of ␣-, ␤ 1 -, and ␤ 2 -subunits. The composition of sodium channels in cardiac muscle, however, has not been defined, and disagreement exists over which ␤-subunits are expressed in the myocytes. Some investigators have demonstrated ␤ 1 expression in heart. Others have not detected any auxiliary subunits. On the basis of Northern blot analysis of total RNA, ␤ 2 expression has been thought to be exclusive to neurons and absent from cardiac muscle. Methods and Results-The goal of this study was to define the subunit composition of cardiac sodium channels in myocytes. We show that cardiac sodium channels are composed of ␣-, ␤ 1 -, and ␤ 2 -subunits. Nav1.5 and Nav1.1 are expressed in myocytes and are associated with ␤ 1 -and ␤ 2 -subunits. Immunocytochemical localization of Nav1.1, ␤ 1 , and ␤ 2 in adult heart sections showed that these subunits are expressed at the Z lines, as shown previously for Nav1.5. Coexpression of Nav1.5 with ␤ 2 in transfected cells resulted in no detectable changes in sodium current. Conclusions-Cardiac sodium channels are composed of ␣-(Nav1.1 or Nav1.5), ␤ 1 -, and ␤ 2 -subunits. Although ␤ 1 -subunits modulate cardiac sodium channel current, ␤ 2 -subunit function in heart may be limited to cell adhesion.

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

“…7C), and connexin-43 (Fig. 7C,6I, 6J) were localized to the intercalated disks, consistent with previous studies [11,23,29]. We found similar results in studies on acutely dissociated ventricular myocytes performed in parallel (not shown).…”

“…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.…”

“…Other groups have reported that coexpression of β1 and Na v 1.5 results in increased I Na density with no detectable effects on gating [35,38]. Some groups have reported modulation of channel sensitivity to lidocaine block with subtle changes in gating properties in response to β1 expression [39], while others have reported significant shifts in the voltage-dependence of steady-state inactivation [29,40] or the rate of recovery from inactivation [41]. The most interesting result of heterologous expression studies in terms of the present data is the finding that β1 coexpression decreases I NaP in HEK cells [42], implying that the loss of β1 expression increases I NaP , consistent with our in vivo results.…”

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

“…In line with other studies demonstrating T‐tubule remodeling in HF, we observed less deep Z grooves in TAC cardiomyocytes in addition to less clearly identifiable T‐tubule openings. Apart from the cardiac sodium channel Na V 1.5, neuronal sodium channel isoforms (ie, Na V 1.1, Na V 1.3, and Na V 1.6) are also thought to populate the T tubules 29, 30, 31, 32. Studies on expression and function of neuronal sodium channel isoforms during HF have shown varied results, most likely because of variations in species (rat, rabbit, dog) and HF model (pressure and/or volume overload and embolizations) used, with the most consistent observation comprising an upregulation of Na V 1.1 5, 23, 33.…”