Modulation of cardiac Na+ current phenotype by β1-subunit expression

Abstract

Na+ current (I(Na)) is smaller, activates and inactivates more slowly, and displays less negative voltage dependence of inactivation in the neonatal rat than in the adult rat. We have observed very similar changes when I(Na) is recorded as a function of time in culture in mouse atrial tumor (AT-1) cells. The differences between mature and immature I(Na) are reminiscent of those observed when skeletal muscle Na+ channel α subunits are expressed alone (immature) or with the β1 subunit (mature). In the present experiments, we tested the hypothesis that suppression of β1-subunit expression by antisense oligonucleotides would prevent the development of a mature I(Na). The mouse β1 subunit was cloned from an AT-1 cDNA library and found to be identical to that in the rat at 216/218 amino acids. AT-1 cells exposed to anti-β1 antisense oligonucleotides displayed an immature I(Na) at day 8 in culture, whereas untreated cells or cells exposed to sense oligonucleotides displayed a mature I(Na). This result was observed with 2 different oligonucleotides, and neither affected the rapidly activating component of the delayed rectifier K+ current, another current recorded in AT-1 cells. These findings indicate that in these cells, the gating of I(Na) is modulated by β1 expression and that α-β1 coexpression is required for the development of a mature cardiac I(Na) phenotype.