Akt-mediated cardiomyocyte survival pathways are compromised by Gαq-induced phosphoinositide 4,5-bisphosphate depletion

Amy L. Howes, Jane F. Arthur, Tong Zhang, Shigeki Miyamoto, John W. Adams, Gerald W. Dorn, Elizabeth A. Woodcock, Joan Heller Brown

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Expression of the wild type α subunit of Gq (G qWT) in cardiomyocytes induces hypertrophy, whereas a constitutively active Gαq subunit (GqQ209L) induces apoptosis. Akt phosphorylation increases with GqWT expression but is markedly attenuated in cardiomyocytes expressing GqQ209L or in those expressing GqWT and treated with agonist. A membrane-targeted Akt rescues GqQ209L-expressing cardiomyocytes from apoptotic cell death. In contrast, leukemia inhibitory factor fails to activate Akt or promote cell survival in these cells. Association of Akt and PDK-1 with the membrane is also diminished in GqQ209L-expressing cardiomyocytes. Phosphatidylinositol 3,4,5-trisphosphate (PIP3), the primary regulator of Akt, increases significantly in GqWT-expressing cells but not in cardiomyocytes expressing GqQ209L. Levels of phosphatidylinositol 4,5-bisphosphate (PIP2), the immediate precursor of PIP3, are also markedly lower in G qQ209L-expressing compared to control cells. Expression of a G qQ209L mutant that has diminished capacity to activate phospholipase C does not decrease PIP2 or Akt or induce apoptosis. In transgenic mice with cardiac Gαq overexpression, heart failure and increased cardiomyocyte apoptosis develop during the peripartal period. Akt phosphorylation and PIP2 levels decrease concomitantly. Our findings suggest that an Akt-mediated cell survival pathway is compromised by the diminished availability of PIP2 elicited by pathological levels of Gq activity.

Original languageEnglish
Pages (from-to)40343-40351
Number of pages9
JournalJournal of Biological Chemistry
Issue number41
StatePublished - Oct 10 2003


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