Endothelin-1-stimulated InsP3-induced Ca2+ release is a nexus for hypertrophic signaling in cardiac myocytes.
Ca(2+) elevations are fundamental to cardiac physiology-stimulating contraction and regulating the gene transcription that underlies hypertrophy. How Ca(2+) specifically controls gene transcription on the background of the rhythmic Ca(2+) increases required for contraction is not fully understood. Here we identify a hypertrophy-signaling module in cardiac myocytes that explains how Ca(2+) discretely regulates myocyte hypertrophy and contraction. We show that endothelin-1 (ET-1) stimulates InsP(3)-induced Ca(2+) release (IICR) from perinuclear InsP(3)Rs, causing an elevation in nuclear Ca(2+). Significantly, we show that IICR, but not global Ca(2+) elevations associated with myocyte contraction, couple to the calcineurin (CnA)/NFAT pathway to induce hypertrophy. Moreover, we found that activation of the CnA/NFAT pathway and hypertrophy by isoproterenol and BayK8644, which enhance global Ca(2+) fluxes, was also dependent on IICR and nuclear Ca(2+) elevations. The activation of IICR by these activity-enhancing mediators was explained by their ability to stimulate secretion of autocrine/paracrine ET-1.
Higazi
Daniel R
DR
Laboratory of Molecular Signalling, Babraham Institute, Cambridge, UK.
Fearnley
Claire J
CJ
Drawnel
Faye M
FM
Talasila
Amarnath
A
Corps
Elaine M
EM
Ritter
Oliver
O
McDonald
Fraser
F
Mikoshiba
Katsuhiko
K
Bootman
Martin D
MD
Roderick
H Llewelyn
HL
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D049108:Cell Enlargement; D002467:Cell Nucleus / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013552:Swine; D014162:Transfection
D019332:Endothelin-1; D015544:Inositol 1,4,5-Trisphosphate; D019703:Calcineurin; D002118:Calcium