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Volume 16, Number 22, Issue of November 15, 1996 pp. 7117-7127
Copyright ©1996 Society for Neuroscience

Molecular Determinants of ₁ Subunit-Induced Gating Modulation in Voltage-Dependent Na⁺ Channels

Received June 25, 1996; revised Aug. 20, 1996; accepted Aug. 30, 1996.

Naomasa Makita, Paul B. Bennett, and Alfred L. George Jr.

Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2372

Recombinant brain, skeletal muscle, and heart voltage-gated Na⁺ channel  subunits differ in their functional responses to an accessory ₁ subunit when coexpressed in Xenopus oocytes. We exploited the distinct ₁ subunit responses observed for the human heart (hH1) and human skeletal muscle (hSkM1) isoforms to identify determinants of this response. Chimeric  subunits were constructed by exchanging the S5-S6 interhelical loops of each domain between hH1 and hSkM1 and then examined for effects on inactivation induced by coexpressed ₁ subunit in oocytes. Substitution of single S5-S6 loops in either domain 1 (D1/S5-S6) or domain 4 (D4/S5-S6) of hSkM1 by the corresponding segments of hH1 produced channels that exhibited an attenuated response to coexpressed ₁ subunit. Substitutions of both D1/S5-S6 and D4/S5-S6 in hSkM1 by the corresponding loops from hH1 completely abolished the effects of the ₁ subunit on inactivation. The reciprocal chimera in which both D1/S5-S6 and D4/S5-S6 from hSkM1 were transplanted into hH1 exhibited significant ₁ responsiveness (accelerated inactivation). The region within D4/S5-S6 that conferred ₁ responsiveness was determined to reside primarily within an extracellular loop between the putative pore-forming segment SS2 and D4/S6. Gating modulation was also demonstrated using a chimeric  subunit consisting of the extracellular domains of ₁ and the transmembrane and C-terminal domains of the rat brain ₂ subunit. These results suggest that the D1/S5-S6 and D4/S5-S6 loops in the  subunit and the extracellular domain of the ₁ subunit are important determinants of the ₁ subunit-induced gating modulation in Na⁺ channels.

Key words: Na⁺ channel; ion channel gating; subunit interaction; electrophysiology; human ion channels; heart; skeletal muscle; hH1; hSkM1; SCN4A; SCN5A

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