J. Gen. Physiol., Volume 113, Number 5, May 1, 1999 661-678

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

Haodong Xu, Weinong Guo, and Jeanne M. Nerbonne

From the Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

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 _decay = 85 ± 2 ms); a slowly (mean ± SEM _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 _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.

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