The β2-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3′-kinase

Recent studies have shown that chronic beta -adrenergic receptor (beta -AR) stimulation alters cardiac myocyte survival in a receptor subtype-specific manner. We examined the effect of selective beta (1)- and beta (2)-AR subtype stimulation on apoptosis induced by hypoxia or H2O2 in rat neonatal cardiac myocytes. Although neither beta (1)- nor beta (2)-AR stimulation had any significant effect on the basal level of apoptosis, selective beta (2)-AR stimulation protected myocytes from apoptosis. beta (2)-AR stimulation markedly increased mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activation as well as phosphatidylinositol-3'-kinase (PI-3K) activity and Akt/protein kinase B phosphorylation. beta (1)-AR stimulation also markedly increased MAPK/ERK activation but only minimally activated PI-3K and Akt, Pretreatment with pertussis toxin blocked beta (2)-AR-mediated protection from apoptosis as well as the beta (2)-AR-stimulated changes in MAPK/ERK, PI-3K, and Akt/protein kinase B. The selective PI-3K inhibitor, LY 294002, also blocked beta (2)-AR-mediated protection, whereas inhibition of MAPK/ERK activation at an inhibitor concentration that blocked agonist-induced activation but not the basal level of activation had no effect on beta (2)-AR-mediated protection. These findings demonstrate that beta (2)-ARs activate a PI-3K-dependent, pertussis toxin-sensitive signaling pathway in cardiac myocytes that is required for protection from apoptosis-inducing stimuli often associated with ischemic stress.