Apoptotic signaling through the beta-adrenergic receptor - A new G(s) effector pathways

Stimulation of beta-adrenergic receptor normally results in signaling by th e heterotrimeric G protein G(s), leading to the activation of adenylyl cycl ase, production of cAMP, and activation of cAMP-dependent protein kinase (P KA), Here we report that cell death of thymocytes can be induced after stim ulation of beta-adrenergic receptor, or by addition of exogenous cAMP. Apop totic cell death in both cases was observed with the appearance of terminal deoxynucleotidyl transferase-mediated UTP end labeling reactivity and the activation of caspase-3 in S49 T cells. Using thymocytes deficient in eithe r G alpha(s) or PKA, we find that engagement of beta-adrenergic receptors i nitiated a G alpha(s)-dependent, PKA-independent pathway leading to apoptos is, This alternative pathway involves Src family tyrosine kinase Lck. Furth ermore, we show that Lck protein kinase activity can be directly stimulated by purified G alpha(s). Our data reveal a new signaling pathway for G alph a(s), distinct from the classical PKA pathway, that accounts for the apopto tic action of beta-adrenergic receptors.