Stable co-expression of hKCNQ1 and hKCNE1 in HEK-293 cells reconstitutes a native-like IKs (HEK-IKs) allowing adrenergic modulation of the current by stimulation of endogenous receptors in the host cell line. HEK-IKs was enhanced 2- to 4-fold by isoproterenol (EC50 =13 nM), forskolin (10 µM) or cpt-cAMP (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 2nd order Hodgkin-Huxley (H-H) gating model incorporating a fast and a slow gate each independent of each other in scale and adrenergic response, a "heterodimer" model. Macroscopically, -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-IKs was observed only at pulse frequencies exceeding 3 Hz. Rate dependent accumulation of IKs at high pulsing rate had two phases, an initial staircase like 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-IKs appeared at lower pulse frequencies, and was slightly enhanced (~ 25%) over control.