ELECTROPHYSIOLOGICAL AND PHARMACOLOGICAL CORRESPONDENCE BETWEEN KV4.2CURRENT AND RAT CARDIAC TRANSIENT OUTWARD CURRENT

Objective: The transient outward current (I-TO) plays an important rol e in early repolarization and overall time course of the cardiac actio n potential. At least two K+ channel alpha-subunits cloned from cardia c tissue (Kv1.4 and Kv4.2) encode rapidly inactivating channels. The g oal of this study was to determine functional and pharmacological prop erties of Kv4.2 expressed in mammalian cells, especially those that wo uld differentiate between both isoforms in comparison to native I-TO. Methods: Both Kv4.2 and Kv1.4 isoforms were stably expressed in mouse L-cell lines, and expressed currents were studied using whole-cell vol tage clamp techniques. Results: The expressed Kv4.2 currents displayed fast inactivation with a half-inactivation potential of -41 mV. Recov ery from inactivation was rapid (tau(recov) = 160 ms at -90 mV) and st rongly voltage-dependent. Flecainide (10 mu M) had minimal effects on Kv1.4 currents, but reduced Kv4.2 peak current by 53% and increased th e apparent rate of inactivation consistent with open channel block. Qu inidine (10-20 mu M) reduced the peak current and accelerated the appa rent rate of inactivation in both isoforms. The Kv4.2 current displaye d use-dependent unblock in the presence of 4-AP. Conclusions: The func tional properties of Kv4.2, especially the flecainide sensitivity, res emble those of I-TO in rat (and human) myocytes better than those of K v1.4. These results provide the necessary functional support for the h ypothesis that Kv4.2 is a major isoform contributing to cardiac I-TO, consistent with independent biochemical and molecular evidence that in dicates that Kv4.2 is readily detected in rat myocytes.