Editorials |
From the Department of Medicine I (A.S.B., S.K.), University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany; and the Department of Cardiology (A.S.B.), Johns Hopkins University, Baltimore, Md.
Correspondence to Stefan Kääb, MD, Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, 81366 Munich, Germany. E-mail Stefan.Kaab{at}med.uni-muenchen.de
See related article, pages 386393
Key Words: MAP Kinases signal transduction transient outward current auxiliary subunit
| Introduction |
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50% reduction was observed in cardiomyocytes from heterozygous animals, indicating that KChIP2 can quantitatively regulate Ito1.5 In line with this finding, KChIP2 mRNA typically distributes across the myocardial wall in a fashion paralleling the gradient of the transient outward current with fast recovery from inactivation encoded by Kv4 channels, with largest concentrations in subepicardium (EPI) and smallest in subendocardium (ENDO) in human and canine hearts.6 This suggests that KChIP2 is the limiting factor in cell surface expression of Ito1 channels, rather than the pore-forming Kv4 subunits which are expressed at equal levels across the ventricular wall in these species. In addition, KChIP2 is also greatly reduced in pathologic conditions with diminished Ito1 current density like heart failure and atrial fibrillation, further suggesting that KChIP2 is involved in controlling Kv4-mediated current levels.7 However, even though the discovery of this auxiliary subunit advanced our understanding of the regional gradients of Ito1 in health and disease, little was known about the regulatory elements upstream of KChIP2. | Regulatory Pathways of Cardiac KChIP2 Expression |
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The observations of Jia and Takimoto raise as many questions as they answer: What are signaling molecules upstream of MAPK (eg, MEKK1, MEK4/7, MEK1/2, small G proteins)? What are the downstream targets of MAPKs mediating transcriptional downregulation of KChIP2? In this respect, it is interesting to note that the transcription factor CREB, which is a target of ERK phosphorylation, has been shown to bind to the KChIP2 promoter region.9 Moreover, ERK has recently also been recognized to regulate Ito1 by direct phosphorylation of the pore-forming Kv4.2 subunit.10 Additional mechanisms, including phosphorylation by tyrosine kinases11 and mRNA degradation of Kv4.3 mRNA by angiotensin II and phenylephrine12 have also been shown to affect Ito1 density. To sort out the relative contribution of all these regulatory mechanisms affecting alpha- and beta-subunits of Ito1 channels will be a challenging task.
| Is MAPK Also Controlling Ito1 Expression in the Human Heart? |
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So far, there is no experimental data to show that MAPKs are involved in the regulation of Ito1 channels in the human heart. However, there is circumstantial evidence to suggest that activation of MAPK pathways may be implicated in the generation of the transmural gradient of Ito1, as ERK activity is significantly greater in human ENDO compared with EPI.14 Therefore, one could hypothesize that high ENDO levels of activated ERK inhibit Kv4-mediated current in ENDO, whereas substantially less inhibition of steady-state Ito1 levels occurs in EPI. Additionally, regulation of Ito1 density via MAPK pathways could also play a significant role in heart failure. Even though the activation status of JNK in end-stage human heart failure is still a matter of debate,15 there is accumulating evidence that ERK1 is upregulated by mechanical stress, as this is the case in end-stage human heart failure.16 Activation of stress-activated MAP kinases could therefore contribute to diminished Ito1 by transcriptional downregulation of KChIP2. Given that activation of stress-activated MAP kinases has been observed to be a part of important cellular signaling events mediated through adrenergic receptors,17 one could speculate that the reduction of Ito1 in heart failure is a result of the altered neurohumoral environment in the failing heart.
What can we expect in the future? Given the plethora of possible regulatory mechanisms in macromolecular ion channel complexes, almost certainly, greater complexity is yet to come. Fortunately, understanding this complexity will generate a more detailed knowledge of homeostatic mechanisms of ion channel regulation and hence, cardiac electrophysiology. In this sense, the article of Jia and Takimoto8 can be viewed an important contribution toward achieving this goal.
| Acknowledgments |
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| Footnotes |
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| References |
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3. Kim LA, Furst J, Gutierrez D, Butler MH, Xu S, Goldstein SA, Grigorieff N. Three-dimensional structure of I(to); Kv4.2-KChIP2 ion channels by electron microscopy at 21 Angstrom resolution. Neuron. 2004; 41: 513519.[CrossRef][Medline] [Order article via Infotrieve]
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7. Barth A, Zwermann L, Kääb S, Näbauer M. KChIP2 mRNA downregulation in human atrial and ventricular myocardium in heart failure and atrial fibrillation may limit functional Ito expression. Circulation. 2002; 106: 90.
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10. Schrader LA, Birnbaum SG, Nadin BM, Ren Y, Bui D, Anderson AE, Sweatt JD ERK/MAPK Regulates the Kv4.2 Potassium Channel by Direct Phosphorylation of the Pore-forming Subunit. Am J Physiol Cell Physiol. 2005.
11. Wang Y, Kumar R, Wagner MB, Cheng J, Mishra M, Joyner RW. Regulation of transient outward current in human atrial myocytes by protein tyrosine kinase pathway. J Cardiovasc Electrophysiol. 2002; 13: 927935.[CrossRef][Medline] [Order article via Infotrieve]
12. Zhang TT, Takimoto K, Stewart AF, Zhu C, Levitan ES. Independent regulation of cardiac Kv4.3 potassium channel expression by angiotensin II and phenylephrine. Circ Res. 2001; 88: 476482.
13. Dixon JE, McKinnon D. Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. Circ Res. 1994; 75: 252260.
14. Baba HA, Stypmann J, Grabellus F, Kirchhof P, Sokoll A, Schafers M, Takeda A, Wilhelm MJ, Scheld HH, Takeda N, Breithardt G, Levkau B. Dynamic regulation of MEK/Erks and Akt/GSK-3beta in human end-stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism. Cardiovasc Res. 2003; 59: 390399.
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16. Takeishi Y, Huang Q, Abe J, Che W, Lee JD, Kawakatsu H, Hoit BD, Berk BC, Walsh RA. Activation of mitogen-activated protein kinases and p90 ribosomal S6 kinase in failing human hearts with dilated cardiomyopathy. Cardiovasc Res. 2002; 53: 131137.
17. McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science. 2000; 290: 15741577.
Related Article:
Circ. Res. 2006 98: 386-393.
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