Four Kinetically Distinct Depolarization-activated K⁺ Currents in Adult Mouse Ventricular Myocytes

In the experiments here, the time- and voltage-dependent properties of the Ca²⁺-independent, depolarization-activated K⁺ currents in adult mouse ventricular myocytes were characterized in detail. In the majority (65 of 72, ≈ 90%) of cells dispersed from the ventricles, analysis of the decay phases of the outward currents revealed three distinct K⁺ current components: a rapidly inactivating, transient outward K⁺ current, I_to,f (mean ± SEM τ_decay = 85 ± 2 ms); a slowly (mean ± SEM τ_decay = 1,162 ± 29 ms) inactivating K⁺ current, I_K,slow; and a non inactivating, steady state current, I_ss. In a small subset (7 of 72, ≈ 10%) of cells, I_to,f was absent and a slowly inactivating (mean ± SEM τ_decay = 196 ± 7 ms) transient outward current, referred to as I_to,s, was identified; the densities and properties of I_K,slow and I_ss in I_to,s-expressing cells are indistinguishable from the corresponding currents in cells with I_to,f. Microdissection techniques were used to remove tissue pieces from the left ventricular apex and from the ventricular septum to allow the hypothesis that there are regional differences in I_to,f and I_to,s expression to be tested directly. Electrophysiological recordings revealed that all cells isolated from the apex express I_to,f (n = 35); I_to,s is not detected in these cells (n = 35). In the septum, by contrast, all of the cells express I_to,s (n = 28) and in the majority (22 of 28, 80%) of cells, I_to,f is also present. The density of I_to,f (mean ± SEM at +40 mV = 6.8 ± 0.5 pA/pF, n = 22) in septum cells, however, is significantly (P < 0.001) lower than I_to,f density in cells from the apex (mean ± SEM at +40 mV = 34.6 ± 2.6 pA/pF, n = 35). In addition to differences in inactivation kinetics, I_to,f, I_to,s, and I_K,slow display distinct rates of recovery (from inactivation), as well as differential sensitivities to 4-aminopyridine (4-AP), tetraethylammonium (TEA), and Heteropoda toxin-3. I_K,slow, for example, is blocked selectively by low (10–50 μM) concentrations of 4-AP and by (≥25 mM) TEA. Although both I_to,f and I_to,s are blocked by high (>100 μM) 4-AP concentrations and are relatively insensitive to TEA, I_to,f is selectively blocked by nanomolar concentrations of Heteropoda toxin-3, and I_to,s (as well as I_K,slow and I_ss) is unaffected. I_ss is partially blocked by high concentrations of 4-AP or TEA. The functional implications of the distinct properties and expression patterns of I_to,f and I_to,s, as well as the likely molecular correlates of these (and the I_K,slow and I_ss) currents, are discussed.