Calcineurin Contributes to the Enhancing Effect of Adenosine on Nerve Growth Factor-Induced Neurite Outgrowth via the Decreased Duration of p38 Mitogen-Activated Protein Kinase Phosphorylation

Department of Pathobiological Science, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan.
Journal of Pharmacological Sciences (Impact Factor: 2.36). 06/2004; 95(1):124-31. DOI: 10.1254/jphs.95.124
Source: PubMed


Adenosine enhances nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. We found that adenosine increases NGF-induced phosphorylation of extracellular signal-regulated kinase (ERK), but decreases the duration of phosphorylation of p38 mitogen-activated protein (MAP) kinase. Therefore, we further examined the involvement of protein phosphatase in these effects of adenosine. FK506, a specific calcineurin inhibitor, inhibited the enhancing effect of adenosine on the NGF-induced neurite outgrowth and increased the duration of p38 MAP kinase phosphorylation without affecting ERK phosphorylation. These results suggest that adenosine decreases the duration of p38 MAP kinase via calcineurin activation, which contributes to the enhancement of NGF-induced neurite outgrowth.

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    • "While the phosphorylation of p38MAPK is necessary for neural differentiation [27, 28], the phosphorylation of p38MAPK inhibits this process [29]. Thus, the results above suggested that the phosphorylation of p38MAPK could promote or inhibit neurite outgrowth depending on the experimental conditions. "
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    ABSTRACT: Components from Dendranthema × grandiflorum cv. “Mottenohoka” that promote neurite outgrowth of PC12 cells were identified and the mechanism of neurite outgrowth stimulated by isolated components was studied. Components that promoted the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2) of PC12 cells were isolated. From various structural analyses, the active components were identified as acacetin and luteolin. The effects of acacetin or luteolin on PC12 cells were evaluated by electro-blotting and immunostaining. Slight neurite outgrowth in PC12 cells was observed within 2 days of culture after stimulation by luteolin or acacetin. However, NGF-stimulation induced remarkable neurite outgrowth in comparison. Neurite outgrowth by luteolin or acacetin was significantly enhanced by pretreatment with SB203580 (a p38MAPK inhibitor). The results of this study into the phosphorylation of ERK 1/2 and p38MAPK by flavonoids suggest that the inhibition of p38MAPK phosphorylation may effectively enhance neurite outgrowth.
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    • "Clearly, given its nuclear localization and its effects on chromatin structure and transcription factor activation , MSK1 would most likely actuate ERK-dependent neuronal morphological plasticity via a transcriptional-dependent mechanism . Here, it is worth noting that, in addition to functioning via the ERK/MAPK cascade, MSK1 is also activated by p38, and signaling via p38 has been shown to affect (both facilitate and repress) neurite outgrowth (Muroi et al. 2004; Kamata et al. 2007; Kano et al. 2007) and spinogenesis (Sugiura et al. 2009). Clearly, additional studies examining whether the effects of MSK1 on neuronal morphology are driven by ERK/MAPK, p38 or both are merited. "
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    • "These findings are in agreement with other groups who have reported synergistic enhancement of NGF-induced neurite outgrowth by adenosine (Muroi et al., 2004), the adenosine analog 5=-N-ethylcarboxamideadenosine (Guroff et al., 1981) and intracellular cAMP (Heidemann et al., 1985; Charles et al., 2003). Differential regulation of GAP-43 and ␤III tubulin expression by NGF and hypoxia was observed in the present study. "
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