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A novel signaling pathway for -adrenergic receptor-mediated activation of phosphoinositide 3-kinase in H9c2 cardiomyocytes

Department of Pediatrics, Women & Infant's Hospital of Rhode Island, Brown Medical School, Providence, Rhode Island

Submitted 1 December 2006 ; accepted in final form 10 March 2007

Stimulation of cardiac -adrenergic receptors (-AR) activates both the G_s- and G_i-coupled signaling cascades, including the phosphoinositide 3 kinase (PI3K) pathway, that have important physiological implications. Multiple isoforms of PI3K exist in the heart. The goals of this study were to examine the intracellular signaling pathways linking -AR to PI3K and to identify the PI3K isoform mediating this transactivation in a cardiac context. Acute -AR stimulation with isoproterenol resulted in increased tyrosine kinase-associated PI3K activity and phosphorylation of Akt and p70S6K in H9c2 cardiomyocytes. Cotreatment with ICI-118,551, but not CGP-20712, abolished the increase in PI3K activity, suggesting a ₂-AR-mediated event. PI3K activation was also abrogated by cotreatment with pertussis toxin, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2, a selective Src-family tyrosine kinases inhibitor), or AG-1296 [selective platelet-derived growth factor receptor (PDGFR) inhibitor] but not with an inhibitor for protein kinase A, protein kinase C, Ras, adenylyl cyclase, epidermal growth factor receptor, or insulin-like growth factor-1 receptor. -AR stimulation induced an increase in tyrosine phosphorylation of PDGFR, which was abolished by inhibition of Src either by PP2 or small interfering RNA. Moreover, H9c2 cardiomyocytes stably transfected with a vector expressing a G sequestrant peptide derived from the COOH-terminus of -AR kinase-1 failed to activate PI3K after -AR stimulation, suggesting G is required for the transactivation. Furthermore, acute -AR stimulation in vivo resulted in increases in PDGFR-associated PI3K and PI3K isoform activities but not the activities of other isoforms (PI3K, -, -) in adult mouse heart. Taken together, these data provide in vitro and in vivo evidence for a novel mechanism of -AR-mediated transactivation of cardiac PI3K via sequential involvement of G_i/G, Src, and PDGFR.

G_i/G; platelet-derived growth factor receptor; Src

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