Yz. Zou et al., Isoproterenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin, CIRCULATION, 104(1), 2001, pp. 102-108
Citations number
38
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background-Extracellular signal-regulated kinases (ERKs) and calcineurin ha
ve been reported to play important roles in the development of cardiac hype
rtrophy. We examined hen the relation between calcineurin and ERKs in cardi
omyocytes.
Methods and Results-Isoproterenol activated ERKs in cultured cardiomyocytes
of neonatal rats, and the activation was abolished by chelation of extrace
llular Ca2+ with EGTA, blockade of L-type Ca2+ channels with nifedipine, or
depletion of intracellular Ca2+ stores with thapsigargin. Isoproterenol-in
duced activation of ERKs was also significantly suppressed by calcineurin i
nhibitors in cultured cardiomyocytes as well as in the hearts of mice. Isop
roterenol failed to activate ERKs in either the cultured cardiomyocytes or
the hearts of mice that overexpress the dominant negative mutant of calcine
urin. Isoproterenol elevated intracellular Ca2+ levels at both systolic and
diastolic phases and dose-dependently activated calcineurin. Inhibition of
calcineurin also attenuated isoproterenol-stimulated phosphorylation of Sr
c, She, and Raf-l kinase. The immunocytochemistry revealed that calcineurin
was localized in the Z band, and isoproterenol induced translocation of ca
lcineurin and ERKs into the nucleus.
Conclusions-Calcineurin, which is activated by marked elevation of intracel
lular Ca2+ levels by the Ca2+-induced Ca2+ release mechanism, regulates iso
proterenol-induced activation of ERKs in cardiomyocytes.