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

摘要

Experimental data accumulated over the past decade show the emerging importance of the late sodium current (INaL) for the function of both normal, and especially, failing myocardium, in which INaL is reportedly increased. While recent molecular studies identified the cardiac Na⁺ channel (NaCh) α subunit isoform (Nav1.5) as a major contributor to INaL, the molecular mechanisms underlying alterations of INaL in heart failure (HF) are still unknown. Here we tested the hypothesis that INaL 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 performed whole-cell patch-clamp experiments. We found that INaL decay kinetic was 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 α+β2 (τ = 0.52 ± 0.09 s, n=5), compared to cells expressing Nav1.5 alone (τ = 0.54 ± 0.09 s, n=20). Also, β1 but not β2 dramatically increased INaL 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 rightward shift of the steady-state availability curve. We conclude that auxiliary β₁ subunit modulates I_NaL, produced by the human cardiac Na⁺ channel Na_v1.5 by slowing its decay and increasing I_NaL amplitude relative to I_NaT. Because expression of Na_v1.5 reportedly decreases but β₁ remains unchanged in chronic HF, the relatively higher expression of β₁ may contribute to known I_NaL increase in HF via the modulation mechanism found in this study.