Two Functionally Distinct 4-Aminopyridine-sensitive Outward Currents in Rat Atrial Myocytes

In the experiments here, the detailed kinetic properties of the Ca~+-independent, depolarization-activated outward currents (lout) in enzymatically dispersed adult rat atrial myocytes were studied. Although there is only slight attenuation of peak/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 Ira and Ir~ to denote the fast and slow components, respectively, Of/out decay. At all test potentials, Ira inactivates ~ 20-fold more rapidly than Ir~. Neither the decay time constants nor the fraction of/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. Ira recovers from inactivation completely, independent of the recovery of I~, and Ira recovers ~ 20 times faster than I~. The pharmacological properties of I ~ and lr~ 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 Ira and Iv~ 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 Ira and Iv~, as well as the composite outward currents, measured in adult rat atrial myocytes. Address reprint requests to Dr. Jeanne M. Nerbonne, Department of Molecular Biology & Pharmacology, Washington University Medical School, 660 South Euclid Avenue, St. Louis, MO 63110. J. G~N. PHYSIOL. © The Rockefeller University Press. 0022-1295/92/12/1041/27 $2.00 Volume 100 December 1992 1041-1067 1041 on A ril 6, 2017 D ow nladed fom Published December 1, 1992