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Cardiovascular Research 2003 59(1):37-45; doi:10.1016/S0008-6363(03)00357-2
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Increased open probability of single cardiac L-type calcium channels in patients with chronic atrial fibrillation

Role of phosphatase 2A

Gunnar Kleina,*, Frank Schrödera, David Voglera, Arnd Schaefera, Axel Haverichb, Bernhard Schieffera, Thomas Kortea and Helmut Drexlera

aDepartment of Cardiovascular Medicine, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
bDepartment of Cardiovascular Surgery, Hannover Medical School, Hannover, Germany

gunnarklein{at}yahoo.de

* Corresponding author. Tel.: +49-511-532-6524; fax: +49-511-532-8475.

Background: The L-type calcium channel (LCC) plays a crucial role in the electrical remodeling of atrial fibrillation (AF). AF is associated with reduction of L-type calcium current density, due to a transcriptional downregulation of the pore forming alpha1c-subunit of LCC. However, it is unclear, whether this current reduction is related to a decrease in channel number or to alterations in channel function. Hence, we performed a single LCC analysis to assess channel gating and function in human AF. Methods and results: We used the cell-attached patch-clamp technique in isolated atrial human cardiomyocytes of 25 patients with sinus rhythm (SR) and 15 patients with chronic AF. Protein expression of the pore-forming {alpha}1c-subunit of LCC was reduced by 40% in AF. Single channel peak average current was 1.7-fold higher in AF than in SR, due to a 3.1-fold higher open probability of LCC. Since phosphatase 2A (PP2A) is known to preferentially reduce LCC open probability via channel dephosphorylation, we assessed whether PP2A expression or activity is reduced in AF. Okadaic acid, an inhibitor of phosphatases, increased channel open probability in SR, but not in AF. However, Western blot analysis of atrial homogenates of the same patient population revealed unchanged expression of PP2A. Conclusions: Human AF is characterized by increased single LCC activity, due to an increase of channel open probability. The blunted effect of PP2A on LCC as shown by single channel analysis may be related to a reduction of cytosolic PP2A activity or impaired local interaction between PP2A and LCC in AF.

KEYWORDS Arrhythmia (mechanisms); Ca-channel; Single channel currents


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