Modulation of Cardiac Na⁺ Current Phenotype by ß₁-Subunit Expression

From Vanderbilt University School of Medicine, Departments of Medicine and Pharmacology, Nashville, Tenn.

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 subunits are expressed alone (immature) or with the ß₁ subunit (mature). In the present experiments, we tested the hypothesis that suppression of ß₁-subunit expression by antisense oligonucleotides would prevent the development of a mature I_Na. The mouse ß₁ 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-ß₁ 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 ß₁ expression and that -ß₁ coexpression is required for the development of a mature cardiac I_Na phenotype.

Key Words: Na⁺ current • ß subunit • myocyte

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