Modeling of the adrenergic response of the human IKs current (hKCNQ1/hKCNE1) stably expressed in HEK-293 cells

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-IKs), allowing β-adrenergic modulation of the current by stimulation of endogenous receptors in the host cell line. HEK-IKs was enhanced two- to fourfold by isoproterenol (EC50 = 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-IKs 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 kine...