Late Na+ current produced by human cardiac Na+ channel isoform Nav1.5 is modulated by its β1 subunit

Abstract

Experimental data accumulated over the past decade show the emerging importance of the late sodium current (I NaL) for the function of both normal and, especially, failing myocardium, in which I NaL is reportedly increased. While recent molecular studies identified the cardiac Na+ channel (NaCh) α subunit isoform (Nav1.5) as a major contributor to I NaL, the molecular mechanisms underlying alterations of I NaL in heart failure (HF) are still unknown. Here we tested the hypothesis that I NaL is modulated by the NaCh auxiliary β subunits. tsA201 cells were transfected simultaneously with human Nav1.5 (former hH1a) and cardiac β1 or β2 subunits, and whole-cell patch-clamp experiments were performed. We found that I NaL decay kinetics were significantly slower in cells expressing α + β1 (time constant τ = 0.73 ± 0.16 s, n = 14, mean ± SEM, P < 0.05) but remained unchanged in cells expressing α + β2 (τ = 0.52 ± 0.09 s, n = 5), compared with cells expressing Nav1.5 alone (τ = 0.54 ± 0.09 s, n = 20). Also, β1, but not β2, dramatically increased I NaL relative to the maximum peak current, I NaT (2.3 ± 0.48%, n = 14 vs. 0.48 ± 0.07%, n = 6, P < 0.05, respectively) and produced a rightward shift of the steady-state availability curve. We conclude that the auxiliary β1 subunit modulates I NaL, produced by the human cardiac Na+ channel Nav1.5 by slowing its decay and increasing I NaL amplitude relative to I NaT. Because expression of Nav1.5 reportedly decreases but β1 remains unchanged in chronic HF, the relatively higher expression of β1 may contribute to the known I NaL increase in HF via the modulation mechanism found in this study.