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, de polarization-activated K+ currents in adult mouse ventricular myocytes were characterized in detail. Ill the majority (65 of 72, approximate to 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,I-f (mean +/- SEM T-decay = 85 +/- 2 ms); a slowly (mean +/- SEM T-decay = 1,162 +/- 29 ms) inactivating K+ current, I-K,I-slow; and a non inactivating, steady state current, I-ss. In a small subset (7 of 72, approximate to 10%) of cells, I-to,I-f,was absent and a slowly inactivating (mean +/- SEM tau(decay) = 196 +/- 7 ms) transient outward current, referred to as I-to,I-s, was identified; the densities and properties of I-K,I-slow and I-ss in I-to,I-s-expressing cells are indistinguishable from the corresponding currents in cells with I-to,I-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,I-f and I-to,I-s expression to be tested directly. Electrophysiological recordings released that all cells isolated fi um the apex express I-to,I-f (n = 35); I-to,I-s is not detected ill these cells (n = 35). In the septum, by contrast, all of the cells express I-to,I-s (n = 28) and in the majority (22 of 28, 80%) of cells, I-to,I-s, is also present. The density of I-to,I-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,I-f density in cells from the apex (mean +/- SEM at +40 mV =,34.6 +/- 2.0 pA/pF, n = 35). In addition tu differences in inactivation kinetics, I-to,I-f, I-to,I-s, and I-K,I-slow display distinct rates of recovery (from inactivation), as well as differential sensitivities to 4-aminopyridine ( 4-AP), tetraethylammonium (TEX), and Heteropoda toxin-3. I-K,I-slow, for example, is blocked selectively by low (10-50 mu M) concentrations of 4-AP and by (greater than or equal to 25 mM) TEA. Although both I-to,I-f and I-to,I-s are blocked by high (>100 mu M) (4-AP) concentrations and are relatively insensitive to TEA, I-to,I-f is selectively blocked by nanomolar concentrations of Heteropoda toxin-3, and I-to,I-s (as well as I-K,I-slow and I-ss) is unaffected. I-ss is partially blocked by high concentrations of 4-AP or TEA. The functional implications of thr distinct properties and expression patterns of I-to,I-f and I-to,I-s, as well as the likely molecular correlates of these (and the I-K,I-slow, and I-ss) currents, are discussed.