title: Atrial tachycardia induces remodelling of muscarinic receptors and their coupled potassium currents in canine left atrial and pulmonary vein cardiomyocytes.
abstract: OBJECTIVE
  Both parasympathetic tone and atrial tachycardia (AT) remodelling of ion channels play important roles in atrial fibrillation (AF) pathophysiology. Different muscarinic cholinergic receptor (mAChR) subtypes (M2, M3, M4) in atrial cardiomyocytes are coupled to distinct K+-currents (called IKM2, IKM3, IKM4, respectively). Pulmonary veins (PVs) are important in AF and differential cholinergic current responses are a potential underlying mechanism. This study investigated AT-induced remodelling of mAChR subtypes and K+-currents in left-atrial (LA) and PV cardiomyocytes.
  
  
  METHODS
  Receptor expression was assayed by western blot. IKM2, IKM3 and IKM4 were recorded with whole-cell patch-clamp in LA and PV cardiomyocytes of nonpaced control dogs and dogs after 7 days of AT-pacing (400 bpm).
  
  
  RESULTS
  Current densities of IKM2, IKM3 and IKM4 were significantly reduced by AT-pacing in LA and PV cardiomyocytes. PV cardiomyocyte current-voltage relations were similar to LA for all three cholinergic currents, both in control and AT remodelling. Membrane-protein expression levels corresponding to M2, M3 and M4 subtypes were decreased significantly (by about 50%) after AT pacing. Agonist concentration-response relations for all three currents were unaffected by AT pacing.
  
  
  CONCLUSIONS
  AT downregulated all three mAChR-coupled K+-current subtypes, along with corresponding mAChR protein expression. These changes in cholinergic receptor-coupled function may play a role in AF pathophysiology. Cholinergic receptor-coupled K+-currents in PV cardiomyocytes were similar to those in LA under control and AT-pacing conditions, suggesting that differential cholinergic current properties do not explain the role of PVs in AF.
authors.affiliation: Department of Medicine, Université de Montréal and Research Center, Montreal Heart Institute, Quebec, Canada.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Yeh
authors.forename: X
authors.initials: X
authors.lastname: Qi
authors.forename: A
authors.initials: A
authors.lastname: Shiroshita-Takeshita
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Maguy
authors.forename: D
authors.initials: D
authors.lastname: Chartier
authors.forename: T
authors.initials: T
authors.lastname: Hebert
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D015536:Down-Regulation; D022062:Electrophysiologic Techniques, Cardiac; D005071:Evoked Potentials; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D011667:Pulmonary Veins / Q000378:metabolism* / Q000473:pathology; D011976:Receptors, Muscarinic / Q000096:biosynthesis / Q000378:metabolism*; D013612:Tachycardia, Ectopic Atrial / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D011976:Receptors, Muscarinic