Submitted on March 28, 2008
Revised on August 13, 2008
Accepted on August 24, 2008
Basal and IGF-1-dependent regulation of potassium channels by MAP kinases and PI-3 kinase during eccentric cardiac hypertrophy
Leyla Y. Teos1, Aiqiu Zhao1, Zikiar Alvin1, Graham G Laurence1, Chuanfu Li2, and Georges E. Haddad1*
1 Howard University
2 East Tennessee State University
* To whom correspondence should be addressed. E-mail: ghaddad{at}howard.edu.
The IK and IK1 channels, responsible for the action potential repolarization and resting potential respectively, are altered during cardiac hypertrophy. Activation of insulin-like growth factor-1 (IGF-1) during hypertrophy may affect channel activity. The aim was to examine the modulatory effects of IGF-1 on IK and IK1 through MAPK and PI-3K pathways during hypertrophy. Using specific inhibitors for ERK1/2 (PD98059), p38 MAPK (SB203580) and PI-3K/Akt (LY294002), western blot and whole-cell patch-clamp was conducted on sham and aorto-caval shunt-induced hypertrophy adult rats' myocytes. Basal activation levels of MAPKs and Akt were increased during hypertrophy. Acute IGF-1 (10-8M) enhanced basal activation levels of these kinases in normal hearts; but only that of Akt in hypertrophied ones. IK and IK1 activities were lowered by IGF-1. Inhibition of ERK1/2, p38 MAPK or Akt reduced basal IK activity by 70%, 32% or 50% respectively in normal cardiomyocytes vs. 53%, 34% or 52% in hypertrophied ones. However, basal activity of IK1 was reduced by 45%, 48% or 45% in the former vs. 63%, 43% or 24% in the latter. Inhibition of either MAPKs or Akt alleviated IGF-1 effects on IK and IK1. We conclude that basal IK and IK1 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-1-stimulated ones towards Akt.
