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(Circulation. 2004;110:2651-2657.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

L-Type Ca²⁺ Current Downregulation in Chronic Human Atrial Fibrillation Is Associated With Increased Activity of Protein Phosphatases

T. Christ, MD; P. Boknik, PhD; S. Wöhrl, MSc; E. Wettwer, PhD; E.M. Graf, PhD; R.F. Bosch, MD; M. Knaut, MD; W. Schmitz, MD; U. Ravens, MD; D. Dobrev, MD

From the Department of Pharmacology (T.C., E.W., E.M.G., U.R., D.D.) and Cardiovascular Centre (M.K.), Dresden University of Technology, Dresden; Department of Pharmacology (P.B., W.S.), University of Münster, Münster; and Department of Cardiology, University of Tübingen, Tübingen (W.S., R.F.B.), Germany.

Correspondence to Dr Dobromir Dobrev, Fetscherstr. 74, 01307 Dresden, Germany. E-mail dobrev{at}rcs.urz.tu-dresden.de

Received February 26, 2004; de novo April 30, 2004; accepted June 2, 2004.

Background— Although downregulation of L-type Ca²⁺ current (I_Ca,L) in chronic atrial fibrillation (AF) is an important determinant of electrical remodeling, the molecular mechanisms are not fully understood. Here, we tested whether reduced I_Ca,L in AF is associated with alterations in phosphorylation-dependent channel regulation.

Methods and Results— We used whole-cell voltage-clamp technique and biochemical assays to study regulation and expression of I_Ca,L in myocytes and atrial tissue from 148 patients with sinus rhythm (SR) and chronic AF. Basal I_Ca,L at +10 mV was smaller in AF than in SR (–3.8±0.3 pA/pF, n=138/37 [myocytes/patients] and –7.6±0.4 pA/pF, n=276/86, respectively; P<0.001), though protein levels of the pore-forming _1c and regulatory ß_2a channel subunits were not different. In both groups, norepinephrine (0.01 to 10 µmol/L) increased I_Ca,L with a similar maximum effect and comparable potency. Selective blockers of kinases revealed that basal I_Ca,L was enhanced by Ca²⁺/calmodulin-dependent protein kinase II in SR but not in AF. Norepinephrine-activated I_Ca,L was larger with protein kinase C block in SR only, suggesting decreased channel phosphorylation in AF. The type 1 and type 2A phosphatase inhibitor okadaic acid increased basal I_Ca,L more effectively in AF than in SR, which was compatible with increased type 2A phosphatase but not type 1 phosphatase protein expression and higher phosphatase activity in AF.

Conclusions— In AF, increased protein phosphatase activity contributes to impaired basal I_Ca,L. We propose that protein phosphatases may be potential therapeutic targets for AF treatment.

Key Words: myocytes • fibrillation, atrial • calcium • phosphatases

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