Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal K_ATP channels

Reducing the ATP sensitivity of the sarcolemmal ATP-sensitive K ⁺ (K_ATP) channel is predicted to lead to active channels in normal metabolic conditions and hence cause shortened ventricular action potentials and reduced myocardial inotropy. We generated transgenic (TG) mice that express an ATP-insensitive K_ATP channel mutant [Kir6.2(ΔN2-30,K185Q)] under transcriptional control of the α-myosin heavy chain promoter. Strikingly, myocyte contraction amplitude was increased in TG myocytes (15.68 ± 1.15% vs. 10.96 ± 1.49%), even though K_ATP channels in TG myocytes are very insensitive to inhibitory ATP. Under normal metabolic conditions, steady-state outward K ₊ currents measured under whole cell voltage clamp were elevated in TG myocytes, consistent with threshold K_ATP activation, but neither the monophasic action potential measured in isolated hearts nor transmembrane action potential measured in right ventricular muscle preparations were shortened at physiological pacing cycles. Taken together, these results suggest that there is a compensatory remodeling of excitation-contraction coupling in TG myocytes. Whereas there were no obvious differences in other K⁺ conductances, peak L-type Ca²⁺ current (I_Ca) density (-16.42 ± 2.37 pA/pF) in the TG was increased compared with the wild type (-8.43 ± 1.01 pA/pF). Isoproterenol approximately doubled both I_Ca and contraction amplitude in wild-type myocytes but failed to induce a significant increase in TG myocytes. Baseline and isoproterenol-stimulated cAMP concentrations were not different in wild-type and TG hearts, suggesting that the enhancement of I_Ca in the latter does not result from elevated cAMP. Collectively, the data demonstrate that a compensatory increase in I_Ca counteracts a mild activation of ATP-insensitive K_ATP channels to maintain the action potential duration and elevate the inotropic state of TG hearts.