The β ₂ -Adrenergic Receptor Delivers an Antiapoptotic Signal to Cardiac Myocytes Through G _i -Dependent Coupling to Phosphatidylinositol 3′-Kinase

Abstract

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 H(2)O(2) 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.

Stimulation of protein kinase B and p70 S6 kinase by the histamine H1 receptor in DDT1MF‐2 smooth muscle cells

“…An increasing number of other studies have also reported that members of the GPCR superfamily activate PKB, including m1 and m2 muscarinic receptors, adenosine A 1 and A 3 receptors, b 2 and b 3 adrenoceptors and the CB 1 cannabinoid receptor (Murga et al, 1998;Gerhardt et al, 1999;Chesley et al, 2000;Germack & Dickenson, 2000;Go mez et al, 2000;Gao et al, 2001). It is interesting to note that b 2 and b 3 adrenoceptor-mediated activation of PKB was inhibited by pretreatment with pertussis toxin and PI-3K inhibitors.…”

Dysfunction of Platelet-derived Growth Factor Receptor α (PDGFRα) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

“…Our observations may also be extrapolated to other demyelinating diseases, such as multiple sclerosis, where demyelination could lead to the availability of myelin debris, transforming myelin-derived sulfatides into environmental toxins (31, 89 -91) that may impair remyelination. In this regard, other myelin components, such as myelin-associated glycoprotein, myelin oligodendrocyte glycoprotein, and Nogo A, are known to exert inhibitory functions, decreasing the regenerative capacity of the brain (92)(93)(94).…”

Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

“…AChsensitive K ϩ (K ACh ) gives rise to an outward K ϩ current at membrane potentials corresponding to the AP plateau (43). In summary, there are at least three signaling pathways that can, therefore, account for the CCh-induced negative inotropy: 1) activation of the inwardly rectifying current I K ACh and APD shortening (20,54); 2) reduction in AC turnover and cAMP levels (18); and 3) activation of PI3K activity to reduce I CaL (10).…”