Dissection of the voltage-activated potassium outward currents in adult mouse ventricular myocytes: I_to,f, I_to,s, I _K,slow1, I_K,slow2, and I_ss

Voltage-activated outward K⁺ currents (I_Kv) are essential for cardiac repolarization and are major factors in the electrophysiological remodeling and arrhythmias seen in heart disease. Mouse models have been useful for understanding cardiac electrophysiology. However, previous methods for separating and quantifying the components of I_Kv in mouse myocardium have yielded inconsistencies. In this study, we developed a statistically rigorous method to uniquely quantify various I_Kv in adult mouse ventricular myocytes, and concluded that tri-exponential functions combined with depolarizing pulses of duration greater than 20 s are essential to adequately separate the different I_Kv components. This method enabled us to reliably dissect the kinetic components of the decay phase of I_Kv into fast (I_to), intermediate (K_V1.5- encoded I_K,slow1) and slow (K_V2-encoded I _K,slow2) components. The most rapid kinetic phase, I_to, can be further dissected into fast (K_V4-encoded I_to,f) and slow (K_V1.4-encoded I_to,s) components by measuring recovery from inactivation, voltage-dependence of activation and sensitivity to HpTx-2 and 4-AP. The applicability of our dissection method was validated using transgenic mice over-expressing dominant-negative KV1.1 transgene which largely abolished the 4-AP-sensitive portion of I_to (i.e., I_to,s) and the I_K,slow1 component. We also applied our method to Irx5-deficient mice and verified selective elevations of I_to in endocardial myocytes. Our method should prove useful in future electrophysiological studies using mouse.