Affiliation:
1. 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.
Abstract
Background—
Although downregulation of L-type Ca
2+
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 α
1c
and regulatory β
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 Ca
2+
/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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
249 articles.
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