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This Article Full Text Full Text (PDF) All Versions of this Article: 582/3/1205    most recent jphysiol.2007.134809v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Abi-Char, J. Articles by Hatem, S. N. Search for Related Content PubMed PubMed Citation Articles by Abi-Char, J. Articles by Hatem, S. N. Related Collections Cardiovascular

¹ INSERM, Unité 621, Paris 75013, France
² Université Pierre et Marie Curie-Paris6, UMR-S621, Paris 75013, France
³ INSERM, U689, Paris 75018, France
⁴ Université Denis Diderot-Paris7, Centre de recherche cardiovasculaire Lariboisière, Paris 75018, France
⁵ Montreal Heart Institute Research Center and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, Canada H1T 1C8

Membrane lipid composition is a major determinant of cell excitability. In this study, we assessed the role of membrane cholesterol composition in the distribution and function of Kv1.5-based channels in rat cardiac membranes. In isolated rat atrial myocytes, the application of methyl--cyclodextrin (MCD), an agent that depletes membrane cholesterol, caused a delayed increase in the Kv1.5-based sustained component, I_kur, which reached steady state in 7 min. This effect was prevented by preloading the MCD with cholesterol. MCD-increased current was inhibited by low 4-aminopyridine concentration. Neonatal rat cardiomyocytes transfected with Green Fluorescent Protein (GFP)-tagged Kv1.5 channels showed a large ultrarapid delayed-rectifier current (I_Kur), which was also stimulated by MCD. In atrial cryosections, Kv1.5 channels were mainly located at the intercalated disc, whereas caveolin-3 predominated at the cell periphery. A small portion of Kv1.5 floated in the low-density fractions of step sucrose-gradient preparations. In live neonatal cardiomyocytes, GFP-tagged Kv1.5 channels were predominantly organized in clusters at the basal plasma membrane. MCD caused reorganization of Kv1.5 subunits into larger clusters that redistributed throughout the plasma membrane. The MCD effect on clusters was sizable 7 min after its application. We conclude that Kv1.5 subunits are concentrated in cholesterol-enriched membrane microdomains distinct from caveolae, and that redistribution of Kv1.5 subunits by depletion of membrane cholesterol increases their current-carrying capacity.

(Received 18 April 2007; accepted after revision 18 May 2007; first published online 24 May 2007)
Corresponding author S. N. Hatem: INSERM UMR621, Faculté de Médecine Pierre-Marie Curie, 91 boulevard de l'Hôpital, 75013 Paris, France. Email: stephane.hatem{at}chups.jussieu.fr

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