title: Calmodulin kinase II and protein kinase C mediate the effect of increased intracellular calcium to augment late sodium current in rabbit ventricular myocytes.
abstract: An increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) augments late sodium current (I(Na.L)) in cardiomyocytes. This study tests the hypothesis that both Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) mediate the effect of increased [Ca(2+)](i) to increase I(Na.L). Whole cell and open cell-attached patch clamp techniques were used to record I(Na.L) in rabbit ventricular myocytes dialyzed with solutions containing various concentrations of [Ca(2+)](i). Dialysis of cells with [Ca(2+)](i) from 0.1 to 0.3, 0.6, and 1.0 μM increased I(Na.L) in a concentration-dependent manner from 0.221 ± 0.038 to 0.554 ± 0.045 pA/pF (n = 10, P < 0.01) and was associated with an increase in mean Na(+) channel open probability and prolongation of channel mean open-time (n = 7, P < 0.01). In the presence of 0.6 μM [Ca(2+)](i), KN-93 (10 μM) and bisindolylmaleimide (BIM, 2 μM) decreased I(Na.L) by 45.2 and 54.8%, respectively. The effects of KN-93 and autocamtide-2-related inhibitory peptide II (2 μM) were not different. A combination of KN-93 and BIM completely reversed the increase in I(Na.L) as well as the Ca(2+)-induced changes in Na(+) channel mean open probability and mean open-time induced by 0.6 μM [Ca(2+)](i). Phorbol myristoyl acetate increased I(Na.L) in myocytes dialyzed with 0.1 μM [Ca(2+)](i); the effect was abolished by Gö-6976. In summary, both CaMKII and PKC are involved in [Ca(2+)](i)-mediated augmentation of I(Na.L) in ventricular myocytes. Inhibition of CaMKII and/or PKC pathways may be a therapeutic target to reduce myocardial dysfunction and cardiac arrhythmias caused by calcium overload.
authors.affiliation: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, China. mjhua@wust.edu.cn
authors.forename: Jihua
authors.initials: J
authors.lastname: Ma
authors.forename: Antao
authors.initials: A
authors.lastname: Luo
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Wan
authors.forename: Peihua
authors.initials: P
authors.lastname: Zhang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Ren
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.forename: Chunping
authors.initials: C
authors.lastname: Qian
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007211:Indoles; D008301:Maleimides; D020929:Mitogen-Activated Protein Kinase Kinases; D010455:Peptides; D011493:Protein Kinase C; D012964:Sodium; D015222:Sodium Channels; D013449:Sulfonamides; C085903:autocamtide-2; C072105:KN 93; D000096926:Benzenesulfonamides; C088060:bisindolylmaleimide