Fig. 4.

β-Arrestin is recruited to β₁AR by Alp or Car and is required for Alp- or Car-induced ERK activation. (A) HEK293 cells stably expressing FLAG-WTβ₁AR are stimulated with Iso, Alp, Car, or Prop. Alp or Car induces β-arrestin recruitment to the β₁AR. (B) HEK293 cells stably expressing WTβ₁AR are transfected with either FLAG-EGFR and scrambled siRNA (si-Con); or FLAG-EGFR and siRNAs targeting β-arrestin 1 (si-βarr1), β-arrestin 2 (si-βarr2), or β-arrestin1/2 (si-βarr1/2), respectively. Alp- or Car-induced phospho-ERK1/2 is diminished in cells transfected with siRNA targeting the β-arrestins. (C) β₁AR agonists enhance cardiac contractility by G protein-dependent signaling, and they also induce β-arrestin-dependent signaling (Left). However, Alp and Car selectively induce β-arrestin-mediated β₁AR transactivation of EGFR (Right). Alp and Car induce GRK-mediated phosphorylation of β₁AR, and recruitment of β-arrestin and Src. This leads to MMP activation to promote HB-EGF shedding, and subsequent activation of EGFR and its downstream signaling such as ERK. Data represent mean ± SE of at least five independent experiments. *, P < 0.05 vs. NS and Prop or si-Con; †, P < 0.01 vs. si-Con; ‡, P < 0.001 vs. NS and Prop.