MEMBRANE TRANSPORT STRUCTURE FUNCTION AND BIOGENESIS
Role of Sodium Channel Deglycosylation in the Genesis of Cardiac Arrhythmias in Heart Failure*

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We investigated the cellular and molecular mechanisms underlying arrhythmias in heart failure. A genetically engineered mouse lacking the expression of the muscle LIM protein (MLP/−) was used in this study as a model of heart failure. We used electrocardiography and patch clamp techniques to examine the electrophysiological properties of MLP/− hearts. We found that MLP/− myocytes had smaller Na+currents with altered voltage dependencies of activation and inactivation and slower rates of inactivation than control myocytes. These changes in Na+ currents contributed to longer action potentials and to a higher probability of early afterdepolarizations in MLP/− than in control myocytes. Western blot analysis suggested that the smaller Na+ current in MLP/− myocytes resulted from a reduction in Na+ channel protein. Interestingly, the blots also revealed that the α-subunit of the Na+ channel from the MLP/− heart had a lower average molecular weight than in the control heart. Treating control myocytes with the sialidase neuraminidase mimicked the changes in voltage dependence and rate of inactivation of Na+ currents observed in MLP/−myocytes. Neuraminidase had no effect on MLP/− cells thus suggesting that Na+ channels in these cells were sialic acid-deficient. We conclude that deficient glycosylation of Na+ channel contributes to Na+ current-dependent arrhythmogenesis in heart failure.

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Published, JBC Papers in Press, May 21, 2001, DOI 10.1074/jbc.M102548200

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This work was supported by NINDS Grants 1 U54 NS39405-02 (to L. F. S.), RO1 NS38770 (to D. J. B.), RO1 HL67927 (to L. F. S.), NSF-EPSCoR (to L. F. S. and D. J. B.), and RCMI-UPR G12RR-03051 (to L. F. S. and D. J. B.) from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Current address: Dept. of Physiology and Biophysics, University of Washington, Box 357290, Seattle, WA 98195-7290.

Current address: Dept. of Biology, Georgia State University, 24 Peach Tree Ave., Atlanta, GA 30303.