title: Role of the calcium-independent transient outward current I(to1) in shaping action potential morphology and duration.
abstract: The Kv4.3-encoded current (I:(Kv4.3)) has been identified as the major component of the voltage-dependent Ca(2+)-independent transient outward current (I:(to1)) in human and canine ventricular cells. Experimental evidence supports a correlation between I:(to1) density and prominence of the phase 1 notch; however, the role of I:(to1) in modulating action potential duration (APD) remains unclear. To help resolve this role, Markov state models of the human and canine Kv4.3- and Kv1.4-encoded currents at 35 degrees C are developed on the basis of experimental measurements. A model of canine I:(to1) is formulated as the combination of these Kv4.3 and Kv1.4 currents and is incorporated into an existing canine ventricular myocyte model. Simulations demonstrate strong coupling between L-type Ca(2+) current and I:(Kv4.3) and predict a bimodal relationship between I:(Kv4.3) density and APD whereby perturbations in I:(Kv4.3) density may produce either prolongation or shortening of APD, depending on baseline I:(to1) current level.
authors.affiliation: Department of Biomedical Engineering, Whitaker Biomedical Engineering Institute, the Center for Computational Medicine & Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Greenstein
authors.forename: R
authors.initials: R
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Po
authors.forename: G F
authors.initials: GF
authors.lastname: Tomaselli
authors.forename: R L
authors.initials: RL
authors.lastname: Winslow
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004285:Dogs; D017930:Genes, Reporter; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020407:Internet; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D051665:Kv1.4 Potassium Channel; D008390:Markov Chains; D008955:Models, Cardiovascular; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011930:Reaction Time; D051672:Shal Potassium Channels; D014584:User-Computer Interface
chemical_list: C496977:KCNA4 protein, human; C497021:KCND3 protein, human; D051665:Kv1.4 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D002118:Calcium