Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation

doi:10.1016/j.cardiores.2007.02.009

Cardiovascular Research 2007 74(3):426-437; doi:10.1016/j.cardiores.2007.02.009

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Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated I_K,ACh channels in patients with chronic atrial fibrillation

Niels Voigt^a, Adina Friedrich^a, Manja Bock^b, Erich Wettwer^a, Torsten Christ^a, Michael Knaut^c, Ruth H. Strasser^b, Ursula Ravens^a and Dobromir Dobrev^a^,*

^aDepartment of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany
^bDepartment of Cardiology, Dresden University of Technology, Dresden, Germany
^cDepartment of Cardiosurgery, Dresden University of Technology, Dresden, Germany

^* Corresponding author. Fetscherstr. 74, 01307 Dresden, Germany. Tel.: +49 351 4586279; fax: +49 351 4586315. Email address: dobrev{at}rcs.urz.tu-dresden.de

Objective: In chronic atrial fibrillation (cAF) the potassiumcurrent I_K,ACh develops agonist-independent constitutive activity.We hypothesized that abnormal phosphorylation-dependent regulationunderlies the constitutive I_K,ACh activity.

Methods: We used voltage-clamp technique and biochemical assaysto study I_K,ACh regulation in atrial appendages from 61 sinusrhythm (SR), 11 paroxysmal AF (pAF), and 33 cAF patients.

Results: Compared to SR basal current was higher in cAF only,whereas the muscarinic receptor (2 µmol/L carbachol)-activatedI_K,ACh was smaller in pAF and cAF. In pAF the selective I_K,AChblocker tertiapin abolished the muscarinic receptor-activatedI_K,ACh but excluded agonist-independent constitutive I_K,AChactivity. Blockade of type-2A phosphatase and the subsequentshift to increased muscarinic receptor phosphorylation (andinactivation) reduced muscarinic receptor-activated I_K,ACh inSR but not in cAF, pointing to an impaired function of G-protein-coupledreceptor kinase. Using subtype-selective kinase inhibitors wefound that in SR the muscarinic receptor-activated I_K,ACh requiresphosphorylation by protein kinase G (PKG), protein kinase C(PKC), and calmodulin-dependent protein kinase II (CaMKII),but not by protein kinase A (PKA). In cAF, constitutive I_K,AChactivity results from abnormal channel phosphorylation by PKCbut not by PKG or CaMKII, whereas the additional muscarinicreceptor-mediated I_K,ACh activation occurs apparently withoutinvolvement of these kinases. In cAF, the higher protein levelof PKC ${varepsilon}$ but not PKC ${alpha}$ , PKCβ₁ or PKC ${delta}$ is likely to contributeto the constitutive I_K,ACh activity.

Conclusions: The occurrence of constitutive I_K,ACh activityin cAF results from abnormal PKC function, whereas the muscarinicreceptor-mediated I_K,ACh activation does not require the contributionof PKG, PKC or CaMKII. Selective drug targeting of constitutivelyactive I_K,ACh channels may be suitable to reduce the abilityof AF to become sustained.

KEYWORDS Fibrillation; Atrium; Potassium channels; Kinases; Phosphatases

Time for primary review 31 days

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