This Article Full Text Full Text (PDF) All Versions of this Article: 110/17/2651    most recent 01.CIR.0000145659.80212.6Av1 Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Christ, T. Articles by Dobrev, D. Search for Related Content PubMed PubMed Citation Articles by Christ, T. Articles by Dobrev, D. Related Collections Cell signalling/signal transduction Ion channels/membrane transport Arrhythmias, clinical electrophysiology, drugs

(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

This article has been cited by other articles:

				Y.-G. Sun, Y.-X. Cao, W.-W. Wang, S.-F. Ma, T. Yao, and Y.-C. Zhu Hydrogen sulphide is an inhibitor of L-type calcium channels and mechanical contraction in rat cardiomyocytes Cardiovasc Res, June 17, 2008; (2008) cvn140v2. [Abstract] [Full Text] [PDF]

				B. J.J.M. Brundel, L. Ke, A.-J. Dijkhuis, X. Qi, A. Shiroshita-Takeshita, S. Nattel, R. H. Henning, and H. H. Kampinga Heat shock proteins as molecular targets for intervention in atrial fibrillation Cardiovasc Res, June 1, 2008; 78(3): 422 - 428. [Abstract] [Full Text] [PDF]

				D. R. Van Wagoner Evaluating the impact of atrial dilatation on atrial calcium cycling Eur. Heart J., May 1, 2008; 29(9): 1084 - 1085. [Full Text] [PDF]

				S. Dinanian, C. Boixel, C. Juin, J.-S. Hulot, A. Coulombe, C. Rucker-Martin, N. Bonnet, B. Le Grand, M. Slama, J.-J. Mercadier, et al. Downregulation of the calcium current in human right atrial myocytes from patients in sinus rhythm but with a high risk of atrial fibrillation Eur. Heart J., May 1, 2008; 29(9): 1190 - 1197. [Abstract] [Full Text] [PDF]

				S. Nattel, B. Burstein, and D. Dobrev Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications Circ Arrhythmia Electrophysiol, April 1, 2008; 1(1): 62 - 73. [Full Text] [PDF]

				H. Tsujikawa, Y. Song, M. Watanabe, H. Masumiya, S. A. Gupte, R. Ochi, and T. Okada Cholesterol depletion modulates basal L-type Ca2+ current and abolishes its -adrenergic enhancement in ventricular myocytes Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H285 - H292. [Abstract] [Full Text] [PDF]

				P. Kirchhof, A. Auricchio, J. Bax, H. Crijns, J. Camm, H.-C. Diener, A. Goette, G. Hindricks, S. Hohnloser, L. Kappenberger, et al. Outcome parameters for trials in atrial fibrillation: executive summary: Recommendations from a consensus conference organized by the German Atrial Fibrillation Competence NETwork (AFNET) and the European Heart Rhythm Association (EHRA) Eur. Heart J., November 2, 2007; 28(22): 2803 - 2817. [Abstract] [Full Text] [PDF]

				P. Kirchhof, A. Auricchio, J. Bax, H. Crijns, J. Camm, H.-C. Diener, A. Goette, G. Hindricks, S. Hohnloser, L. Kappenberger, et al. Outcome parameters for trials in atrial fibrillation: Recommendations from a consensus conference organized by the German Atrial Fibrillation Competence NETwork and the European Heart Rhythm Association Europace, November 1, 2007; 9(11): 1006 - 1023. [Abstract] [Full Text] [PDF]

				C. A. Carnes, P. M. L. Janssen, M. L. Ruehr, H. Nakayama, T. Nakayama, H. Haase, J. A. Bauer, M. K. Chung, I. M. Fearon, A. M. Gillinov, et al. Atrial Glutathione Content, Calcium Current, and Contractility J. Biol. Chem., September 21, 2007; 282(38): 28063 - 28073. [Abstract] [Full Text] [PDF]

				N. Voigt, A. Friedrich, M. Bock, E. Wettwer, T. Christ, M. Knaut, R. H. Strasser, U. Ravens, and D. Dobrev Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation Cardiovasc Res, June 1, 2007; 74(3): 426 - 437. [Abstract] [Full Text] [PDF]

				S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]

				S. C.M. Choisy, L. A. Arberry, J. C. Hancox, and A. F. James Increased Susceptibility to Atrial Tachyarrhythmia in Spontaneously Hypertensive Rat Hearts Hypertension, March 1, 2007; 49(3): 498 - 505. [Abstract] [Full Text] [PDF]

				S. Cardin, E. Libby, P. Pelletier, S. Le Bouter, A. Shiroshita-Takeshita, N. Le Meur, J. Leger, S. Demolombe, A. Ponton, L. Glass, et al. Contrasting Gene Expression Profiles in Two Canine Models of Atrial Fibrillation Circ. Res., February 16, 2007; 100(3): 425 - 433. [Abstract] [Full Text] [PDF]

				C. Rucker-Martin, P. Milliez, S. Tan, X. Decrouy, M. Recouvreur, R. Vranckx, C. Delcayre, J.-F. Renaud, I. Dunia, D. Segretain, et al. Chronic hemodynamic overload of the atria is an important factor for gap junction remodeling in human and rat hearts Cardiovasc Res, October 1, 2006; 72(1): 69 - 79. [Abstract] [Full Text] [PDF]

				S. de Haan, M. Greiser, E. Harks, Y. Blaauw, A. van Hunnik, S. Verheule, M. Allessie, and U. Schotten AVE0118, Blocker of the Transient Outward Current (Ito) and Ultrarapid Delayed Rectifier Current (IKur), Fully Restores Atrial Contractility After Cardioversion of Atrial Fibrillation in the Goat Circulation, September 19, 2006; 114(12): 1234 - 1242. [Abstract] [Full Text] [PDF]

				A. El-Armouche, P. Boknik, T. Eschenhagen, L. Carrier, M. Knaut, U. Ravens, and D. Dobrev Molecular Determinants of Altered Ca2+ Handling in Human Chronic Atrial Fibrillation Circulation, August 15, 2006; 114(7): 670 - 680. [Abstract] [Full Text] [PDF]

				P. Molenaar, T. Christ, U. Ravens, and A. Kaumann Carvedilol blocks {beta}2- more than {beta}1-adrenoceptors in human heart Cardiovasc Res, January 1, 2006; 69(1): 128 - 139. [Abstract] [Full Text] [PDF]

				D. Dobrev, A. Friedrich, N. Voigt, N. Jost, E. Wettwer, T. Christ, M. Knaut, and U. Ravens The G Protein-Gated Potassium Current IK,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation Circulation, December 13, 2005; 112(24): 3697 - 3706. [Abstract] [Full Text] [PDF]

				N. Gaborit, M. Steenman, G. Lamirault, N. Le Meur, S. Le Bouter, G. Lande, J. Leger, F. Charpentier, T. Christ, D. Dobrev, et al. Human Atrial Ion Channel and Transporter Subunit Gene-Expression Remodeling Associated With Valvular Heart Disease and Atrial Fibrillation Circulation, July 26, 2005; 112(4): 471 - 481. [Abstract] [Full Text] [PDF]