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Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H1834-45. doi: 10.1152/ajpheart.321.2008. Epub 2008 Aug 29.

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy.

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  • 1Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC 20059, USA.

Abstract

The potassium channels I(K) and I(K1), responsible for the action potential repolarization and resting potential respectively, are altered during cardiac hypertrophy. The activation of insulin-like growth factor-I (IGF-I) during hypertrophy may affect channel activity. The aim was to examine the modulatory effects of IGF-I on I(K) and I(K1) through mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways during hypertrophy. With the use of specific inhibitors for ERK1/2 (PD98059), p38 MAPK (SB203580) and PI3K/Akt (LY294002), Western blot and whole cell patch-clamp were conducted on sham and aorto-caval shunt-induced hypertrophy adult rat myocytes. Basal activation levels of MAPKs and Akt were increased during hypertrophy. Acute IGF-I (10(-8) M) enhanced basal activation levels of these kinases in normal hearts but only those of Akt in hypertrophied ones. I(K) and I(K1) activities were lowered by IGF-I. Inhibition of ERK1/2, p38 MAPK, or Akt reduced basal I(K) activity by 70, 32, or 50%, respectively, in normal cardiomyocytes vs. 53, 34, or 52% in hypertrophied ones. However, basal activity of I(K1) was reduced by 45, 48, or 45% in the former vs. 63, 43, or 24% in the latter. The inhibition of either MAPKs or Akt alleviated IGF-I effects on I(K) and I(K1). We conclude that basal I(K) and I(K1) are positively maintained by steady-state Akt and ERK activities. K+ channels seem to be regulated in a dichotomic manner by acutely stimulated MAPKs and Akt. Eccentric cardiac hypertrophy may be associated with a change in the regulation of the steady-state basal activities of K+ channels towards MAPKs, while that of the acute IGF-I-stimulated ones toward Akt.

PMID:
18757484
PMCID:
PMC2614587
DOI:
10.1152/ajpheart.321.2008
[PubMed - indexed for MEDLINE]
Free PMC Article
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