Role of sodium channel deglycosylation in the genesis of cardiac arrhythmias in heart failure.

Abstract

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 alpha-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.

• Authors: C A Ufret-Vincenty, D J Baro, W J Lederer, H A Rockman, L E Quinones, L F Santana
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 30 Pg. 28197-203 (Jul 27 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11369778 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Sodium Channels
• Sodium
• Neuraminidase

Topics

• Action Potentials
• Animals
• Arrhythmias, Cardiac (etiology, metabolism)
• Blotting, Western
• Disease Models, Animal
• Electrocardiography
• Glycosylation
• Heart Failure (etiology, metabolism)
• Humans
• Mice
• Mice, Transgenic
• Neuraminidase (pharmacology)
• Patch-Clamp Techniques
• Protein Processing, Post-Translational
• Sodium (metabolism)
• Sodium Channels (metabolism)