title: Quantitative analysis of the Ca2+-dependent regulation of delayed rectifier K+current IKsin rabbit ventricular myocytes.
abstract: [Ca2+]ienhanced rabbit ventricular slowly activating delayed rectifier K+current (IKs) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol. Rabbit ventricular rapidly activating delayed rectifier K+current (IKr) amplitude and voltage dependence were unaffected by high [Ca2+]i. When measuring or simulating IKsduring an action potential, IKswas not different during a physiological Ca2+transient or when [Ca2+]iwas buffered to 500 nm.
  
  
  
  The slowly activating delayed rectifier K+current (IKs) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca2+([Ca2+]i) and β-adrenergic receptor (β-AR) stimulation modulate IKsamplitude and kinetics, but details of these important IKsregulators and their interaction are limited. We assessed the [Ca2+]idependence of IKsin steady-state conditions and with dynamically changing membrane potential and [Ca2+]iduring an AP. IKswas recorded from freshly isolated rabbit ventricular myocytes using whole-cell patch clamp. With intracellular pipette solutions that controlled free [Ca2+]i, we found that raising [Ca2+]ifrom 100 to 600 nm produced similar increases in IKsas did β-AR activation, and the effects appeared additive. Both β-AR activation and high [Ca2+]iincreased maximally activated tail IKs, negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well-established mathematical model of the rabbit myocyte. In both AP-clamp experiments and simulations, IKsrecorded during a normal physiological Ca2+transient was similar to IKsmeasured with [Ca2+]iclamped at 500-600 nm. Thus, our study provides novel quantitative data as to how physiological [Ca2+]iregulates IKsamplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca2+]i, in the submembrane or junctional cleft space, is not required to maximize [Ca2+]i-dependent IKsactivation during normal Ca2+transients.
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Daniel C
authors.identifier: 0000-0001-8273-8057
authors.initials: DC
authors.lastname: Bartos
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Stefano
authors.identifier: 0000-0001-8679-665X
authors.initials: S
authors.lastname: Morotti
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Ginsburg
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Eleonora
authors.identifier: 0000-0002-4401-8857
authors.initials: E
authors.lastname: Grandi
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Donald M
authors.identifier: 0000-0002-2237-9483
authors.initials: DM
authors.lastname: Bers
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000502:physiology*; D051668:Delayed Rectifier Potassium Channels / Q000502:physiology*; D006352:Heart Ventricles; D008297:Male; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000502:physiology*
chemical_list: D051668:Delayed Rectifier Potassium Channels; D002118:Calcium
keywords: action potential; cardiac electrophysiology; delayed rectifier current; intracellular calcium; potassium channel; rabbit; voltage-gated channels