Apoptotic signaling through the α-adrenergic receptor: A new G(s) effector pathway

Stimulation of β-adrenergic receptor normally results in signaling by the heterotrimeric G protein G(s), leading to the activation of adenylyl cyclase, production of cAMP, and activation of cAMP-dependent protein kinase (PKA). Here we report that cell death of thymocytes can be induced after stimulation of β-adrenergic receptor, or by addition of exogenous cAMP. Apoptotic 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 either Gα(s) or PKA, we find that engagement of β-adrenergic receptors initiated a Gα(s)-dependent, PKA-independent pathway leading to apoptosis. This alternative pathway involves Src family tyrosine kinase Lck. Furthermore, we show that Lck protein kinase activity can be directly stimulated by purified Gα(s). Our data reveal a new signaling pathway for Gα(s), distinct from the classical PKA pathway, that accounts for the apoptotic action of β-adrenergic receptors.