title: Sarcoplasmic reticulum Ca²⁺ release is both necessary and sufficient for SK channel activation in ventricular myocytes.
abstract: SK channels are upregulated in human patients and animal models of heart failure (HF). However, their activation mechanism and function in ventricular myocytes remain poorly understood. We aim to test the hypotheses that activation of SK channels in ventricular myocytes requires Ca(2+) release from sarcoplasmic reticulum (SR) and that SK currents contribute to reducing triggered activity. SK2 channels were overexpressed in adult rat ventricular myocytes using adenovirus gene transfer. Simultaneous patch clamp and confocal Ca(2+) imaging experiments in SK2-overexpressing cells demonstrated that depolarizations resulted in Ca(2+)-dependent outward currents sensitive to SK inhibitor apamin. SR Ca(2+) release induced by rapid application of 10 mM caffeine evoked repolarizing SK currents, whereas complete depletion of SR Ca(2+) content eliminated SK currents in response to depolarizations, despite intact Ca(2+) influx through L-type Ca(2+) channels. Furthermore, voltage-clamp experiments showed that SK channels can be activated by global spontaneous SR Ca(2+) release events Ca(2+) waves (SCWs). Current-clamp experiments revealed that SK overexpression reduces the amplitude of delayed afterdepolarizations (DADs) resulting from SCWs and shortens action potential duration. Immunolocalization studies showed that overexpressed SK channels are distributed both at external sarcolemmal membranes and along the Z-lines, resembling the distribution of endogenous SK channels. In summary, SR Ca(2+) release is both necessary and sufficient for the activation of SK channels in rat ventricular myocytes. SK currents contribute to repolarization during action potentials and attenuate DADs driven by SCWs. Thus SK upregulation in HF may have an anti-arrhythmic effect by reducing triggered activity.
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Terentyev
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Rochira
authors.forename: Radmila
authors.initials: R
authors.lastname: Terentyeva
authors.forename: Karim
authors.initials: K
authors.lastname: Roder
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.forename: Weiyan
authors.initials: W
authors.lastname: Li
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; C496899:Kcnn2 protein, rat; D026902:Potassium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D051640:Small-Conductance Calcium-Activated Potassium Channels; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: arrhythmia; delayed afterdepolarization; heart failure; small conductance calcium activated potassium channel