Cumulative Inactivation of the Outward Potassium Current: a Likely Mechanism Underlying Electrical Memory in Human Atrial Myocytes

The influence of the mode of cell stimulation on the outward K+current (Io) was studied in whole-cell patch-clamped human atrial myocytes. Acceleration of the rate of membrane depolarization at 1 Hz or during prolonged 5-s test pulses at 0.1 Hz increased the rate and extent of Ioinactivation, resulting in enhanced inactivating (4.9±0.6 v 6.3±0.7 pA/pF) and suppressed maintained (5.9±1.2 v 3.2±0.3 pA/pF) current components. These alterations were associated with a leftward shift of the voltage-dependency of Io, and persisted on returning to a control depolarization protocol (750-ms test pulses delivered at 0.1 Hz). The effects of increasing external K+concentrations (40 m 0 ) on the kinetics of Iowere more pronounced following both rapid and prolonged depolarization (changes in It/Iocaused by 40 m 0K+: 8.9±3.5%v 15.5±3.1% before and after prolonged depolarization; and 9.2±1.2%v 15.4±1.7% before and after rapid depolarization). The phosphatase inhibitor, okadaic acid, enhanced the effect of rapid and prolonged depolarization on Iowhereas the inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMK-II) with KN-62 or KN-93, or by intracellular application of the autocamtide-2-related inhibitory peptide, suppressed it. In conclusion, rapid and prolonged membrane depolarization both cause a cumulative increase in the rate and extent of Ioinactivation. This process involves slow potassium channel inactivation mechanisms, is regulated by CaMK-II, and may contribute to the electrical memory of the atrial myocardium.