Role of sodium channel deglycosylation in the genesis of cardiac arrhythmias in heart failure.
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.
Ufret-Vincenty
C A
CA
Institute of Neurobiology, University of Puerto Rico, San Juan, Puerto Rico 00901, USA.
Baro
D J
DJ
Lederer
W J
WJ
Rockman
H A
HA
Quinones
L E
LE
Santana
L F
LF
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004562:Electrocardiography; D006031:Glycosylation; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009439:Neuraminidase / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011499:Protein Processing, Post-Translational; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*
D015222:Sodium Channels; D012964:Sodium; D009439:Neuraminidase