doi: 10.1161/01.RES.0000208057.36708.48
© 2006 American Heart Association, Inc.
Editorials |
MAPK = Mitogen-Activated Protein KChIP2?
Unraveling Signaling Pathways Controlling Cardiac Ito Expression
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@med.uni-muenchen.de
See related article, pages 386–393
Key Words: MAP Kinases • signal transduction • transient outward current • auxiliary subunit
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
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Introduction |
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Reduction in density of the cardiac calcium-independent transient outward potassium current (Ito1) is one of the most consistent findings in electrophysiological remodeling observed in animal models of left ventricular hypertrophy and failure as well as in the human heart under pathological conditions.1 Initially attributed to downregulation of the mRNA of pore-forming Kv4 subunits,2 a more complex picture emerged over time as several auxiliary subunits were identified, offering new potential regulatory elements for controlling Ito1 density. KChIP2 is a dazzling member of this group of beta-subunits which assembles with pore-forming Kv4 subunits in 4:4 complexes to produce native Ito1 channels.3 Several different KChIP2 splice variants are expressed in the human heart and the major KChIP2 isoform (KChIP2c) has been found to boost Ito1 current density and to speed up recovery from inactivation, thereby recapitulating several, albeit not all, features of native Ito1 channels.4 Importantly, myocytes isolated from KChIP2 knock-out mice exhibited a complete, selective loss of Ito1, whereas an
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
Related Article:
Circ. Res. 2006 98: 386-393.