PubMed 21252158

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: KChip2a , Kv1.4 , Kv3.1 , Kv4.2 , Kv4.3

Title: Nuclear factor kappaB downregulates the transient outward potassium current I(to,f) through control of KChIP2 expression.

Authors: Brian K Panama, Desiree Latour-Villamil, Gerrie P Farman, Dongling Zhao, Steffen-Sebastian Bolz, Lorrie A Kirshenbaum, Peter H Backx

Journal, date & volume: Circ. Res., 2011 Mar 4 , 108, 537-43

PubMed link:

The fast transient outward K(+) current (I(to,f)) plays a critical role in early repolarization of the heart. I(to,f) is consistently downregulated in cardiac disease. Despite its importance, the regulation of I(to,f) in disease remains poorly understood.Because the transcription factor nuclear factor (NF)-κB is activated in cardiac hypertrophy and disease, we studied the role of NF-κB in mediating I(to,f) reductions induced by hypertrophy.Culturing neonatal rat ventricular myocytes in the presence of phenylephrine (PE) plus propranolol (Pro), to selectively activate α(1)-adrenergic receptors, caused reductions in I(to,f), as well as KChIP2 and Kv4.3 expression, while increasing Kv4.2 expression. Inhibition of NF-κB, via overexpression of a phosphorylation-deficient mutant of IκBα (IκBαSA) prevented PE/Pro-induced reductions in I(to,f) and KChIP2 mRNA, without affecting Kv4.2 or Kv4.3 expression, suggesting NF-κB mediates the I(to,f) reductions by repressing KChIP2. Indeed, overexpression of the NF-κB activator IκB kinase-β also decreased KChIP2 expression and I(to,f) (despite increasing Kv4.2), whereas IκBαSA overexpression elevated KChIP2 and decreased Kv4.2 levels. In addition, the classic NF-κB activator tumor necrosis factor α also induced NF-κB-dependent reductions of KChIP2 and I(to,f). Finally, inhibition of calcineurin did not prevent PE/Pro-induced reductions in KChIP2.NF-κB regulates KChIP2 and Kv4.2 expression. The reductions in I(to,f) observed following α-adrenergic receptor stimulation or tumor necrosis factor α application require NF-κB-dependent decreases in KChIP2 expression.