NDLI: Modeling of the adrenergic response of the human $I_{Ks}$ current (hKCNQ1/hKCNE1) stably expressed in HEK-293 cells

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Imredy, John P. Penniman, Jacob R. Dech, Spencer J. Irving, Winston D. Salata, Joseph J.
Description	Country affiliation: United States Author Affiliation: Imredy JP ( Safety and Exploratory Pharmacology, Safety Assessment, Merck Research Laboratories, West Point, PA 19486, USA. john_imredy@merck.com)
Abstract	Stable coexpression of human (h)KCNQ1 and hKCNE1 in human embryonic kidney (HEK)-293 cells reconstitutes a nativelike slowly activating delayed rectifier $K^{+}$ current $(HEK-I_{Ks}),$ allowing β-adrenergic modulation of the current by stimulation of endogenous receptors in the host cell line. $HEK-I_{Ks}$ was enhanced two- to fourfold by isoproterenol $(EC_{50}$ = 13 nM), forskolin (10 μM), or 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate (50 μM), indicating an intact cAMP-dependent ion channel-regulating pathway analogous to the PKA-dependent regulation observed in native cardiac myocytes. Activation kinetics of $HEK-I_{Ks}$ were accurately fit with a novel modified second-order Hodgkin-Huxley (H-H) gating model incorporating a fast and a slow gate, each independent of each other in scale and adrenergic response, or a “heterodimer” model. Macroscopically, β-adrenergic enhancement shifted the current activation threshold to more negative potentials and accelerated activation kinetics while leaving deactivation kinetics relatively unaffected. Modeling of the current response using the H-H model indicated that observed changes in gating could be explained by modulation of the opening rate of the fast gate. Under control conditions at nearly physiological temperatures (35°C), rate-dependent accumulation of $HEK-I_{Ks}$ was observed only at pulse frequencies exceeding 3 Hz. Rate-dependent accumulation of $I_{Ks}$ at high pulsing rate had two phases, an initial staircaselike effect followed by a slower, incremental accumulation phase. These phases are readily interpreted in the context of a heterodimeric H-H model with two independent gates with differing closing rates. In the presence of isoproterenol after normalizing for its tonic effects, rate-dependent accumulation of $HEK-I_{Ks}$ appeared at lower pulse frequencies and was slightly enhanced (∼25%) over control.
File Format	HTM / HTML
ISSN	03636135
e-ISSN	15221539
Journal	AJP: Heart and Circulatory Physiology
Issue Number	5
Volume Number	295
Language	English
Publisher	American Physiological Society
Publisher Date	2008-11-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Physiology Discipline Cardiology Ion Channel Gating Kcnq1 Potassium Channel Metabolism Potassium Channels, Voltage-gated Receptors, Adrenergic, Beta Adenylate Cyclase Adrenergic Beta-agonists Pharmacology Cell Line Colforsin Cyclic Amp Analogs & Derivatives Enzyme Activators Drug Effects Isoproterenol Genetics Kinetics Membrane Potentials Models, Cardiovascular Potassium Recombinant Proteins Temperature Thionucleotides Transfection
Alternative Title	Modeling of the adrenergic response of the human IKs current (hKCNQ1/hKCNE1) stably expressed in HEK-293 cells
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Cardiology and Cardiovascular Medicine

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cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists.

Protein kinase C downregulates I(Ks) by stimulating KCNQ1-KCNE1 potassium channel endocytosis.

Gender differences in the slow delayed $(I_{Ks})$ but not in inward $(I_{K1})$ rectifier $K^{+}$ currents of canine Purkinje fibre cardiac action potential: key roles for $I_{Ks},$ β-adrenoceptor stimulation, pacing rate and gender

The role of the $I_{sK}$ protein in the specific pharmacological properties of the $I_{Ks}$ channel complex

Modulation of {beta}-adrenoceptor signaling in the hearts of 4-wk simulated weightlessness rats.

A reassessment of the modulatory role of cyclic AMP in catecholamine secretion by chromaffin cells.

Induction of functional beta-adrenergic receptors in HeLa cells.

Beta-adrenergic stimulation reverses the $I_{Kr}–I_{Ks}$ dominant pattern during cardiac action potential

Protein Kinase C downregulates I Ks by stimulating KCNQ1-KCNE1 potassium channel endocytosis

Modeling of the adrenergic response of the human $I_{Ks}$ current (hKCNQ1/hKCNE1) stably expressed in HEK-293 cells

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cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists.

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