Dual modulation of cell survival and cell death by β₂-adrenergic signaling in adult mouse cardiac myocytes

Abstract

The goal of this study was to determine whether β₁-adrenergic receptor (AR) and β₂-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac β₂-AR can activate both G_s and G_i proteins, whereas cardiac β₁-AR couples only to G_s. To avoid complicated crosstalk between β-AR subtypes, we expressed β₁-AR or β₂-AR individually in adult β₁/β₂-AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of β₁-AR, but not β₂-AR, markedly induced myocyte apoptosis, as indicated by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling or Hoechst staining positive cells and DNA fragmentation. In contrast, β₂-AR (but not β₁-AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G_i, G_{β γ}, or phosphoinositide 3 kinase (PI3K) with pertussis toxin, βARK-ct (a peptide inhibitor of G_{β γ}), or LY294002, respectively. This indicates that β₂-AR activates Akt via a G_i-G_{β γ}-PI3K pathway. More importantly, inhibition of the G_i-G_{β γ}-PI3K-Akt pathway converts β₂-AR signaling from survival to apoptotic. Thus, stimulation of a single class of receptors, β₂-ARs, elicits concurrent apoptotic and survival signals in cardiac myocytes. The survival effect appears to predominate and is mediated by the G_i-G_{β γ}-PI3K-Akt signaling pathway.

• β-adrenergic receptor subtypes
• G proteins
• apoptosis