Published online before print October 12, 2006, doi: 10.1161/01.RES.0000249369.71709.5c
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on August 19, 2005
Revised on September 28, 2006
Accepted on September 28, 2006
Calmodulin Kinase II Inhibition Shortens Action Potential Duration by Upregulation of K+ Currents
Jingdong Li ;
From the Departments of Internal Medicine (J.L., M.E.A.) and Physiology (M.E.A.), University of Iowa, Carver College of Medicine, Iowa City; Department of Cardiology (J.L.), Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; Department of Molecular Biology and Pharmacology (C.M., J.M.N.), Washington University Medical School, St Louis, Mo; Department of Genetics (R.Z.), Stanford University, Calif; and Department of Pharmacology (V.S., J.W.H.), University of Iowa, Iowa City.
* To whom correspondence should be addressed. E-mail: mark-e-anderson{at}uiowa.edu.
The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by elevated intracellular Ca2+ (Ca2+i), and mice with chronic myocardial CaMKII inhibition (Inh) resulting from transgenic expression of a CaMKII inhibitory peptide (AC3-I) unexpectedly showed action potential duration (APD) shortening. Inh mice exhibit increased L-type Ca2+ current (ICa), because of upregulation of protein kinase A (PKA) activity, and decreased CaMKII-dependent phosphorylation of phospholamban (PLN). We hypothesized that CaMKII is a molecular signal linking Ca2+i to repolarization. Whole cell voltage-clamp recordings revealed that the fast transient outward current (Ito,f) and the inward rectifier current (IK1) were selectively upregulated in Inh, compared with wild-type (WT) and transgenic control, mice. Breeding Inh mice with mice lacking PLN returned Ito,f and IK1 to control levels and equalized the APD and QT intervals in Inh mice to control and WT levels. Dialysis of AC3-I into WT cells did not result in increased Ito,f or IK1, suggesting that enhanced cardiac repolarization in Inh mice is an adaptive response to chronic CaMKII inhibition rather than an acute effect of reduced CaMKII activity. Increasing PKA activity, by cell dialysis with cAMP, or inhibition of PKA did not affect IK1 in WT cells. Dialysis of WT cells with cAMP also reduced Ito,f, suggesting that PKA upregulation does not increase repolarizing K+ currents in Inh mice. These findings provide novel in vivo and cellular evidence that CaMKII links Ca2+i to cardiac repolarization and suggest that PLN may be a critical CaMKII target for feedback regulation of APD in ventricular myocytes.
Key words: Ca2+/calmodulin-dependent protein kinase II • calcium signaling • repolarization
Related Article:
- CaM Kinase Inhibition: Apply Directly to the Heart?
- Barry London
Circ. Res. 2006 99: 1027-1028.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  S. Wagner, E. Hacker, E. Grandi, S. L. Weber, N. Dybkova, S. Sossalla, T. Sowa, L. Fabritz, P. Kirchhof, D. M. Bers, et al. Ca/Calmodulin Kinase II Differentially Modulates Potassium Currents Circ Arrhythm Electrophysiol, June 1, 2009; 2(3): 285 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. El-Haou, E. Balse, N. Neyroud, G. Dilanian, B. Gavillet, H. Abriel, A. Coulombe, A. Jeromin, and S. N. Hatem Kv4 Potassium Channels Form a Tripartite Complex With the Anchoring Protein SAP97 and CaMKII in Cardiac Myocytes Circ. Res., March 27, 2009; 104(6): 758 - 769. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. London Understanding Cardiac Calcium Channelopathies Circulation, November 25, 2008; 118(22): 2221 - 2222. [Full Text] [PDF]
|
|
|
|
|
|
W. H. Thiel, B. Chen, T. J. Hund, O. M. Koval, A. Purohit, L.-S. Song, P. J. Mohler, and M. E. Anderson Proarrhythmic Defects in Timothy Syndrome Require Calmodulin Kinase II Circulation, November 25, 2008; 118(22): 2225 - 2234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Xiao, P. Coutu, L. R. Villeneuve, A. Tadevosyan, A. Maguy, S. Le Bouter, B. G. Allen, and S. Nattel Mechanisms Underlying Rate-Dependent Remodeling of Transient Outward Potassium Current in Canine Ventricular Myocytes Circ. Res., September 26, 2008; 103(7): 733 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. F. Couchonnal and M. E. Anderson The Role of Calmodulin Kinase II in Myocardial Physiology and Disease Physiology, June 1, 2008; 23(3): 151 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Livshitz and Y. Rudy Regulation of Ca2+ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2854 - H2866. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Anderson Multiple downstream proarrhythmic targets for calmodulin kinase II: Moving beyond an ion channel-centric focus Cardiovasc Res, March 1, 2007; 73(4): 657 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. London CaM Kinase Inhibition: Apply Directly to the Heart? Circ. Res., November 10, 2006; 99(10): 1027 - 1028. [Full Text] [PDF]
|
|