Role of Sodium Channel Deglycosylation in the Genesis of Cardiac Arrhythmias in Heart Failure

Carmen A. Ufret-Vincenty, Deborah J. Baro, W. Jonathan Lederer, Howard A. Rockman, Luis E. Quiñones, Luis Fernando Santana

Research output: Contribution to journalArticle

96 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)28197-28203
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number30
DOIs
StatePublished - Jul 27 2001
Externally publishedYes

Fingerprint

Sodium Channels
Cardiac Arrhythmias
Heart Failure
Muscle Cells
Neuraminidase
Glycosylation
cysteine and glycine-rich protein 3
Clamping devices
Electric potential
N-Acetylneuraminic Acid
Patch-Clamp Techniques
Electrocardiography
Action Potentials
Molecular Weight
Western Blotting
Chemical activation
Molecular weight

ASJC Scopus subject areas

  • Biochemistry

Cite this

Role of Sodium Channel Deglycosylation in the Genesis of Cardiac Arrhythmias in Heart Failure. / Ufret-Vincenty, Carmen A.; Baro, Deborah J.; Lederer, W. Jonathan; Rockman, Howard A.; Quiñones, Luis E.; Santana, Luis Fernando.

In: Journal of Biological Chemistry, Vol. 276, No. 30, 27.07.2001, p. 28197-28203.

Research output: Contribution to journalArticle

Ufret-Vincenty, Carmen A. ; Baro, Deborah J. ; Lederer, W. Jonathan ; Rockman, Howard A. ; Quiñones, Luis E. ; Santana, Luis Fernando. / Role of Sodium Channel Deglycosylation in the Genesis of Cardiac Arrhythmias in Heart Failure. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 30. pp. 28197-28203.
@article{ffaf6fde7c874015bd6f56d9d677ae10,
title = "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 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.",
author = "Ufret-Vincenty, {Carmen A.} and Baro, {Deborah J.} and Lederer, {W. Jonathan} and Rockman, {Howard A.} and Qui{\~n}ones, {Luis E.} and Santana, {Luis Fernando}",
year = "2001",
month = "7",
day = "27",
doi = "10.1074/jbc.M102548200",
language = "English (US)",
volume = "276",
pages = "28197--28203",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "30",

}

TY - JOUR

T1 - Role of Sodium Channel Deglycosylation in the Genesis of Cardiac Arrhythmias in Heart Failure

AU - Ufret-Vincenty, Carmen A.

AU - Baro, Deborah J.

AU - Lederer, W. Jonathan

AU - Rockman, Howard A.

AU - Quiñones, Luis E.

AU - Santana, Luis Fernando

PY - 2001/7/27

Y1 - 2001/7/27

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0035958924&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035958924&partnerID=8YFLogxK

U2 - 10.1074/jbc.M102548200

DO - 10.1074/jbc.M102548200

M3 - Article

C2 - 11369778

AN - SCOPUS:0035958924

VL - 276

SP - 28197

EP - 28203

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 30

ER -