Rat α2-macroglobulin inhibits NGF-promoted neurite outgrowth, TrK phosphorylation, and gene expression of pheochromocytoma PC12 cells
✍ Scribed by Paek-Gyu Lee; Peter H. Koo
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 226 KB
- Volume
- 57
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Rat alpha-1-macroglobulin (␣ 1 M) and alpha-2-macroglobulin (␣ 2 M) are murine homologs of human ␣ 2 M, and rat ␣ 2 M is generally known as an acute-phase protein. Monoamine-activated forms of human ␣ 2 M have been shown to inhibit various neuronal functions, but the effect of rat ␣ 1 M and acute-phase ␣ 2 M on neurons is largely unknown. In this report, rat serotonin-activated ␣ 2 M (5HT-␣ 2 M) has been demonstrated to inhibit nerve growth factor (NGF)-promoted neurite extension in pheochromocytoma PC12 cells, and we investigated its possible mechanism of action including its effect on NGF-promoted signal transduction and gene expression in these cells. Especially in the absence of NGF, 5HT-␣ 2 M was found to bind to TrkA (the high-affinity receptor for NGF) much better than normal ␣ 2 M (N-␣ 2 M). 5HT-␣ 2 M dose-dependently inhibited NGF-promoted autophosphorylation of TrkA, and decreased the expression of two immediate-early genes (NGFI-A and c-jun) and two delayed-response genes (SCG10 and transin) which are associated with neurite outgrowth in PC12 cells. The unmodified N-␣ 2 M, on the other hand, exhibited very little or no inhibitory effects on neurite extension, Trk phosphorylation, or expression of these genes. The results of this study taken together suggest that monoamine-activated acute-phase rat ␣ 2 M appears to inhibit neurite outgrowth in PC12 cells possibly via its direct binding to TrkA and subsequent blocking of TrkA-mediated signal transduction and gene expression.