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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 5, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn085
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

IKs response to protein kinase A-dependent KCNQ1 phosphorylation requires direct interaction with microtubules

Céline S. Nicolasa,b,c, Kyu-Ho Parka,b,c,1, Aziza El Harchia,b,c,2, Jacques Camonisd, Robert S. Kasse, Denis Escandea,b,c, Jean Mérota,b,c, Gildas Loussouarna,b,c, Françoise Le Bouffanta,b,c and Isabelle Baróa,b,c,*

a Inserm, UMR915, l'institut du thorax, Nantes, F-44035 France
b CNRS, ERL4137, Nantes, F-44035 France
c Université de Nantes, Faculté de Médecine, Nantes, F-44035 France
d Inserm, U830, Institut Curie, Paris, F-75248 France
e Department of Pharmacology, Columbia University Medical Center, 630 W. 168th S., New York, NY 10032, U.S.A

* Corresponding author. Tel.: +33 2 40 41 28 48; fax: +33 2 40 41 29 50. E-Mail address: isabelle.baro{at}nantes.inserm.fr (I. Baró)

Aims: KCNQ1 (alias KvLQT1 or Kv7.1) and KCNE1 (alias IsK or minK) co-assemble to form the voltage-activated K+ channel responsible for IKs - a major repolarizing current in the human heart - and their dysfunction promotes cardiac arrhythmias. The channel is a component of larger macromolecular complexes containing known and undefined regulatory proteins. Thus, identification of proteins that modulate its biosynthesis, localization, activity and/or degradation is of great interest from both a physiological and pathological point of view.

Methods and results: Using a yeast two-hybrid screen, we detected a direct interaction between β-tubulin and the KCNQ1 N-terminus. The interaction was confirmed by co-immunoprecipitation of β-tubulin and KCNQ1 in transfected COS-7 cells and in guinea-pig cardiomyocytes. Using immunocytochemistry, we also found that they co-localized in cardiomyocytes. We tested the effects of microtubule-disrupting and -stabilizing agents (colchicine and taxol, respectively) on the KCNQ1/KCNE1 channel activity in COS-7 cells by means of the permeabilized-patch configuration of the patch-clamp technique. None of these agents altered IKs. In addition, colchicine did not modify the current response to osmotic challenge. On the other hand, the IKs response to protein kinase A (PKA)-mediated stimulation depended on microtubule polymerization in COS-7 cells and in cardiomyocytes. Strikingly, KCNQ1 channel and yotiao phosphorylation by PKA - detected by phospho-specific antibodies - was maintained, as was the association of the two partners.

Conclusions: We propose that the KCNQ1/KCNE1 channel directly interacts with microtubules and that this interaction plays a major role in coupling PKA-dependent phosphorylation of KCNQ1 with IKs activation.

Time for primary review: 31 days

1 K.-H.P. present address: IBBMC, Bâtiment 430, Université de Paris-Sud; F-91405 Orsay, France

2 A.E.H. present address: Dept. of Physiology & Pharmacology, School Of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom


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