title: The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation.
abstract: BACKGROUND
  The molecular mechanism of increased background inward rectifier current (IK1) in atrial fibrillation (AF) is not fully understood. We tested whether constitutively active acetylcholine (ACh)-activated I(K,ACh) contributes to enhanced basal conductance in chronic AF (cAF).
  
  
  RESULTS
  Whole-cell and single-channel currents were measured with standard voltage-clamp techniques in atrial myocytes from patients with sinus rhythm (SR) and cAF. The selective I(K,ACh) blocker tertiapin was used for inhibition of I(K,ACh). Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated I(K,ACh) was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced I(K,ACh) in a concentration-dependent manner with greater potency in cAF than in SR (-logIC50: 9.1 versus 8.2; P<0.05). Basal current contained a tertiapin-sensitive component that was larger in cAF than in SR (tertiapin [10 nmol/L]-sensitive current at -100 mV: cAF, -6.7+/-1.2 pA/pF, n=16/5 [myocytes/patients] versus SR, -1.7+/-0.5 pA/pF, n=24/8), suggesting contribution of constitutively active I(K,ACh) to basal current. In single-channel recordings, constitutively active I(K,ACh) was prominent in cAF but not in SR (channel open probability: cAF, 5.4+/-0.7%, n=19/9 versus SR, 0.1+/-0.05%, n=16/9; P<0.05). Moreover, IK1 channel open probability was higher in cAF than in SR (13.4+/-0.4%, n=19/9 versus 11.4+/-0.7%, n=16/9; P<0.05) without changes in other channel characteristics.
  
  
  CONCLUSIONS
  Our results demonstrate that larger basal inward rectifier K+ current in cAF consists of increased IK1 activity and constitutively active I(K,ACh). Blockade of I(K,ACh) may represent a new therapeutic target in AF.
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Dresden, Germany. dobrev@rcs.urz.tu-dresden.de
authors.forename: D
authors.initials: D
authors.lastname: Dobrev
authors.forename: A
authors.initials: A
authors.lastname: Friedrich
authors.forename: N
authors.initials: N
authors.lastname: Voigt
authors.forename: N
authors.initials: N
authors.lastname: Jost
authors.forename: E
authors.initials: E
authors.lastname: Wettwer
authors.forename: T
authors.initials: T
authors.lastname: Christ
authors.forename: M
authors.initials: M
authors.lastname: Knaut
authors.forename: U
authors.initials: U
authors.lastname: Ravens
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D020517:Atrial Appendage / Q000166:cytology; D001281:Atrial Fibrillation / Q000209:etiology*; D001514:Bee Venoms / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002908:Chronic Disease; D004594:Electrophysiology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics* / Q000502:physiology; D005838:Genotype; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000378:metabolism
chemical_list: D001514:Bee Venoms; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D044387:GTP-Binding Protein beta Subunits; C029738:tertiapin; D002217:Carbachol; D000109:Acetylcholine; D011188:Potassium