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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/H1834    most recent 321.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Teos, L. Y. Articles by Haddad, G. E. PubMed PubMed Citation Articles by Teos, L. Y. Articles by Haddad, G. E.

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

¹Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, District of Columbia; and ²Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee

Submitted 28 March 2008 ; accepted in final form 24 August 2008

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.

phosphatidylinositol 3-kinase; mitogen activated protein kinase; insulin-like growth factor-I