Fig. 5. PrPc-mediated neuroprotective signaling. (A and B) Responses of the cAMP/PKA signaling pathway to the PrR peptide (PrR) in the retina of either wild-type or PrP0/0 mice. Positive controls were either forskolin (FORSK) or a D1-like dopaminergic receptor agonist (6-Chloro-PB). Note the cAMP (A) and PKA (B) responses restricted to wild-type retinal tissue, and the higher basal values in knockout retinas. (C) Western blots for phospho-Elk (top) and loading control with actin (bottom), following treatment of either wild-type or PrP0/0 mouse retinal tissue with the PrR peptide. Note the activation of the Erk pathway restricted to wild-type tissue, as well as the higher basal activity in knockout tissue. (D–F) PrPc-mediated neuroprotective signaling through the cAMP-PKA pathway. Retinal explants from neonatal rats were treated with anisomycin (1 µg/ml), the PrR peptide (PrR 80 µM) in the presence of either 100 µM Rp-cAMP-s (D) or 100 µM Sp-cAMP-s (E), respectively an inhibitor and an activator of cAMP-dependent protein kinase, or in the presence of 30 µM PD98059, an inhibitor of the Erk-activating MEK enzyme (F). Note the reversion of the neuroprotective effect with the PKA inhibitor, and the potentiation of the neuroprotective effect with the Erk pathway inhibitor.