Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy.
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.
Teos
Leyla Y
LY
Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC 20059, USA.
Zhao
Aiqiu
A
Alvin
Zikiar
Z
Laurence
Graham G
GG
Li
Chuanfu
C
Haddad
Georges E
GE