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 (I(o)) 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 I(o) inactivation, 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 I(o), 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 m) on the kinetics of I(o) were more pronounced following both rapid and prolonged depolarization (changes in I(t)/I(o)caused by 40 m m K+: 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 I(o)whereas 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 I(o)inactivation. This process involves slow potassium channel inactivation mechanisms, is regulated by CaMK-II, and may contribute to the electrical memory of the atrial myocardium.
INSERM Unité 460 and Service de chirurgie cardiaque, Groupe Hospitalier Bichat-Claude Bernard and Faculté Xavier Bichat, 75018 Paris, France.
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Tessier
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Godreau
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Vranckx
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Lang-Lazdunski
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Mercadier
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Hatem
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020517:Atrial Appendage / Q000166:cytology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002414:Cations, Monovalent; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D004558:Electric Stimulation; D004594:Electrophysiology; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008875:Middle Aged; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology*; D013997:Time Factors
D002414:Cations, Monovalent; D015221:Potassium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D011188:Potassium