2 FUNCTIONALLY DISTINCT 4-AMINOPYRIDINE-SENSITIVE OUTWARD K+ CURRENTS IN RAT ATRIAL MYOCYTES

In the experiments here, the detailed kinetic properties of the Ca2+-independent, depolarization-activated outward currents (I(out)) in enzymatically dispersed adult rat atrial myocytes were studied. Although there is only slight attenuation of peak I(out), during brief (100 ms) voltage steps, substantial decay is evident during long (10 s) depolarizations. The analyses here reveal that current inactivation is best described by the sum of two exponential components, which we have termed I(Kf) and I(Ks) to denote the fast and slow components, respectively, of I(out) decay. At all test potentials, I(Kf) inactivates approximately 20-fold more rapidly than I(Ks). Neither the decay time constants nor the fraction of I(out) remaining at the end of 10-s depolarizations varies over the potential range of 0 to +50 mV, indicating that the rates of inactivation and recovery from inactivation are voltage independent. I(Kf) recovers from inactivation completely, independent of the recovery of I(ks), and I(Kf) recovers approximately 20 times faster than I(Ks). The pharmacological properties of I(Kf) and I(Ks) are similar: both components are sensitive to 4-aminopyridine (1-5 mM) and both are relatively resistant to externally applied tetraethylammonium (50 mM). Taken together, these findings suggest that I(Kf) and I(Ks) correspond to two functionally distinct K+ currents with similar voltage-dependent properties and pharmacologic sensitivities, but with markedly different rates of inactivation and recovery from inactivation. From the experimental data, several gating models were developed in which voltage-independent inactivation is coupled either to channel opening or to the activation of the individual channel subunits. Experimental testing of predictions of these models suggests that voltage-independent inactivation is coupled to activation, and that inactivation of only a single subunit is required to result in functional inactivation of the channels. This model closely approximates the properties of I(Kf) and I(Ks), as well as the composite outward currents, measured in adult rat atrial myocytes.