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Cardiovascular Research Advance Access first published online on October 26, 2009
This version [Corrected Proof] published online on November 23, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp352
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Tubulin polymerization modifies cardiac sodium channel expression and gating

Simona Casini, Hanno L. Tan, Ilker Demirayak, Carol Ann Remme, Ahmad S. Amin, Brendon P. Scicluna, Houssine Chatyan, Jan M. Ruijter, Connie R. Bezzina, Antoni C.G. van Ginneken and Marieke W. Veldkamp*

Department of Clinical and Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

* Corresponding author. Tel: +31 20 5663269, Fax: +31 20 6975458, Email: m.w.veldkamp{at}amc.uva.nl

Aims: Treatment with the anticancer drug taxol (TXL), which polymerizes the cytoskeleton protein tubulin, may evoke cardiac arrhythmias based on reduced human cardiac sodium channel (Nav1.5) function. Therefore, we investigated whether enhanced tubulin polymerization by TXL affects Nav1.5 function and expression and whether these effects are β1-subunit-mediated.

Methods and results: Human embryonic kidney (HEK293) cells, transfected with SCN5A cDNA alone (Nav1.5) or together with SCN1B cDNA (Nav1.5 + β1), and neonatal rat cardiomyocytes (NRCs) were incubated in the presence and in the absence of 100 µM TXL. Sodium current (INa) characteristics were studied using patch-clamp techniques. Nav1.5 membrane expression was determined by immunocytochemistry and confocal microscopy. Pre-treatment with TXL reduced peak INa amplitude nearly two-fold in both Nav1.5 and Nav1.5 + β1, as well as in NRCs, compared with untreated cells. Accordingly, HEK293 cells and NRCs stained with anti-Nav1.5 antibody revealed a reduced membrane-labelling intensity in the TXL-treated groups. In addition, TXL accelerated INa decay of Nav1.5 + β1, whereas INa decay of Nav1.5 remained unaltered. Finally, TXL reduced the fraction of channels that slow inactivated from 31% to 18%, and increased the time constant of slow inactivation by two-fold in Nav1.5. Conversely, slow inactivation properties of Nav1.5 + β1 were unchanged by TXL.

Conclusion: Enhanced tubulin polymerization reduces sarcolemmal Nav1.5 expression and INa amplitude in a β1-subunit-independent fashion and causes INa fast and slow inactivation impairment in a β1-subunit-dependent way. These changes may underlie conduction-slowing-dependent cardiac arrhythmias under conditions of enhanced tubulin polymerization, e.g. TXL treatment and heart failure.

KEYWORDS Sodium channel; Electrophysiology; Cytoskeleton; Taxol; Arrhythmia

Time for primary review: 14 days


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