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J. Biol. Chem., Vol. 279, Issue 43, 44303-44310, October 22, 2004

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The Sialic Acid Component of the ₁ Subunit Modulates Voltage-gated Sodium Channel Function^*

Daniel Johnson, Marty L. Montpetit, Patrick J. Stocker, and Eric S. Bennett

From the Department of Physiology & Biophysics and Program in Neuroscience, University of South Florida College of Medicine, Tampa, Florida 33612

Voltage-gated sodium channels (Na_v) are responsible for initiation and propagation of nerve, skeletal muscle, and cardiac action potentials. Na_v are composed of a pore-forming subunit and often one to several modulating subunits. Previous work showed that terminal sialic acid residues attached to subunits affect channel gating. Here we show that the fully sialylated ₁ subunit induces a uniform, hyperpolarizing shift in steady state and kinetic gating of the cardiac and two neuronal subunit isoforms. Under conditions of reduced sialylation, the ₁-induced gating effect was eliminated. Consistent with this, mutation of ₁ N-glycosylation sites abolished all effects of ₁ on channel gating. Data also suggest an interaction between the cis effect of sialic acids and the trans effect of ₁ sialic acids on channel gating. Thus, ₁ sialic acids had no effect gating on the of the heavily glycosylated skeletal muscle subunit. However, when glycosylation of the skeletal muscle subunit was reduced through chimeragenesis such that sialic acids did not impact gating, ₁ sialic acids caused a significant hyperpolarizing shift in channel gating. Together, the data indicate that ₁ N-linked sialic acids can modulate Na_v gating through an apparent saturating electrostatic mechanism. A model is proposed in which a spectrum of differentially sialylated Na_v can directly modulate channel gating, thereby impacting cardiac, skeletal muscle, and neuronal excitability.

Received for publication, August 4, 2004 , and in revised form, August 13, 2004.

^* This work was supported in part by a grant from the NIAMS, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Physiology & Biophysics, University of South Florida, College of Medicine, MDC 8, Tampa, FL 33612. Tel.: 813-974-1545; Fax: 813-974-3079; E-mail: esbennet{at}hsc.usf.edu.

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