PACAP activates Rac1 and synergizes with NGF to activate ERK1/2, thereby inducing neurite outgrowth in PC12 cells.
The mechanisms linked to the neuritogenic effect of PACAP acting in synergy with NGF were analyzed in PC12 cells. Recently, we have shown that PACAP synergizes with NGF to stimulate PACAP gene transcription and neurite outgrowth, differentially dependent on both the ERK1/2 and p38 MAP kinase pathways in PC12 cells. This suggests that PACAP modulates mitogen signaling pathways governing cell differentiation, in part through MAP kinase activation and an autocrine mechanism. Here, we studied the mechanism of the underlying neuritogenic actions of PACAP. PACAP induced transient activation of Rac1, a small GTPase involved in neurite outgrowth, in a PI3-kinase-independent manner, and stimulated accumulation of active Rac1 at filamentous actin-rich protrusions on the cell surface to induce subsequent neurite formation. PACAP had no additional effect on the activity of Rac1 beyond the effect of NGF and failed to activate Ras or Cdc42. By contrast, simultaneous treatment with PACAP and NGF acts in synergy to induce prolonged activation of ERK1/2. These results indicate for the first time that PACAP induces activation of Rac1 associated with neurite outgrowth and suggest that the synergistic effect of PACAP and NGF on neurite extension is due to enhanced activation of ERK1/2.
Sakai
Yoshiyuki
Y
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Hashimoto
Hitoshi
H
Shintani
Norihito
N
Katoh
Hironori
H
Negishi
Manabu
M
Kawaguchi
Chihiro
C
Kasai
Atsushi
A
Baba
Akemichi
A
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D022081:Cell Surface Extensions / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004357:Drug Synergism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D016716:PC12 Cells; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D020830:rac1 GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism*
C495403:Adcyap1 protein, rat; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein