title: Role for myosin-V motor proteins in the selective delivery of Kv channel isoforms to the membrane surface of cardiac myocytes.
abstract: BACKGROUND
  Kv1.5 (KCNA5) mediates the ultra-rapid delayed rectifier current that controls atrial action potential duration. Given its atrial-specific expression and alterations in human atrial fibrillation, Kv1.5 has emerged as a promising target for the treatment of atrial fibrillation. A necessary step in the development of novel agents that selectively modulate trafficking pathways is the identification of the cellular machinery controlling Kv1.5 surface density, of which little is yet known.
  
  
  OBJECTIVE
  To investigate the role of the unconventional myosin-V (MYO5A and MYO5B) motors in determining the cell surface density of Kv1.5.
  
  
  RESULTS
  Western blot analysis showed MYO5A and MYO5B expression in the heart, whereas disruption of endogenous motors selectively reduced IKur current in adult rat cardiomyocytes. Dominant negative constructs and short hairpin RNA silencing demonstrated a role for MYO5A and MYO5B in the surface trafficking of Kv1.5 and connexin-43 but not potassium voltage-gated channel, subfamily H (eag-related), member 2 (KCNH2). Live-cell imaging of Kv1.5-GFP and retrospective labeling of phalloidin demonstrated motility of Kv1.5 vesicles on actin tracts. MYO5A participated in anterograde trafficking, whereas MYO5B regulated postendocytic recycling. Overexpression of mutant motors revealed a selective role for Rab11 in coupling MYO5B to Kv1.5 recycling.
  
  
  CONCLUSIONS
  MYO5A and MYO5B control functionally distinct steps in the surface trafficking of Kv1.5. These isoform-specific trafficking pathways determine Kv1.5-encoded IKur in myocytes to regulate repolarizing current and, consequently, cardiac excitability. Therapeutic strategies that manipulate Kv1.5 selective trafficking pathways may prove useful in the treatment of arrhythmias.
authors: From the Department of Pharmacology, University of Michigan, Ann Arbor (S.M.S.-B., E.D.V., L.Z., K.E.R., D.P.M., C.R.F., J.C.M., J.R.M.); Cardiovascular Research Institute Robin Shaw, Department of Medicine, University of California, San Francisco (P.J.C.); and Cedars-Sinai Medical Center, Los Angeles, CA (R.M.S.).
authors: Sarah M
authors: SM
authors: Schumacher-Bass
authors: Eileen D
authors: ED
authors: Vesely
authors: Lian
authors: L
authors: Zhang
authors: Katherine E
authors: KE
authors: Ryland
authors: Dyke P
authors: DP
authors: McEwen
authors: Priscilla J
authors: PJ
authors: Chan
authors: Chad R
authors: CR
authors: Frasier
authors: Jeremy C
authors: JC
authors: McIntyre
authors: Robin M
authors: RM
authors: Shaw
authors: Jeffrey R
authors: JR
authors: Martens
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D018031:Connexin 43 / Q000032:analysis; D000072237:ERG1 Potassium Channel; D004705:Endocytosis; D051638:Ether-A-Go-Go Potassium Channels / Q000032:analysis; D017629:Gap Junctions; D017930:Genes, Reporter; D006329:Heart Conduction System / Q000503:physiopathology; D017136:Ion Transport; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D024701:Myosin Type V / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009218:Myosins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000502:physiology; D000099193:rab11 GTP-Binding Proteins
chemical_list: D018031:Connexin 43; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D051666:Kv1.5 Potassium Channel; D018995:Myosin Heavy Chains; D024701:Myosin Type V; D009218:Myosins; D011188:Potassium; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C543076:GJA1 protein, mouse; C580592:Gja1 protein, rat; C000606913:KCNH2 protein, human; C000606915:Kcnh2 protein, mouse; C000606918:Kcnh2 protein, rat; C588269:Myo5B protein, mouse; C513082:Myo5a protein, mouse
keywords: Kv1.5 potassium channel; arrhythmias, cardiac; connexin 43; heart