Mitogen-activated protein kinases control cardiac KChIP2 gene expression.
Hypertrophied myocardium is associated with reductions in the transient outward K(+) current (Ito) and expression of pore-forming Kv4.2/4.3 and auxiliary KChIP2 subunits. Here we show that KChIP2 mRNA and protein levels are dramatically decreased to 10% to 30% of control levels in the left ventricle of aorta-constricted rats in vivo and phenylephrine (PE)-treated myocytes in vitro. PE also markedly decreases Ito density. Inhibition of protein kinase Cs (PKCs) does not affect the PE-induced reduction in KChIP2 mRNA level, whereas activation of PKC with phorbol ester (phorbol myristate [PMA]) causes a marked reduction in KChIP2 mRNA level. Pharmacological inhibition of MEKs or overexpression of a dominant-negative MEK1 increases the basal KChIP2 mRNA expression and blocks the PMA-induced decrease in auxiliary subunit mRNA level. In addition, a constitutively active MEK1 decreases the basal KChIP2 mRNA level, and PMA causes no further reduction in auxiliary subunit mRNA level in active MEK1-expressing cells. Furthermore, pharmacological inhibition of JNKs or overexpression of a dominant-negative JNK1 prevents the PE-induced, but not PMA-induced, reduction in KChIP2 mRNA expression. These results suggest that downregulation of KChIP2 expression significantly contributes to the hypertrophy-associated reduction in Ito density. They also indicate that the expression of KChIP2 mRNA is controlled by the 2 branches of mitogen-activated protein kinase pathways: JNKs play a predominant role in mediating the PE-induced reduction, whereas the MEK-ERK pathway influences the basal expression and mediates the PKC-mediated downregulation.
Jia
Ying
Y
Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Takimoto
Koichi
K
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D051605:Kv Channel-Interacting Proteins / Q000235:genetics*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function
C496758:Kcnip2 protein, rat; D051605:Kv Channel-Interacting Proteins; D012333:RNA, Messenger; D010656:Phenylephrine; D020928:Mitogen-Activated Protein Kinases