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 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 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.