Rat alpha(2)-macroglobulin inhibits NGF-promoted neurite outgrowth, Trk phosphorylation, and gene expression of pheochromocytoma PC12 cells

Rat alpha-1-macroglobulin (alpha(1)M) and alpha-2-macroglobulin (alpha(2)M) are murine homologs of human alpha(2)M, and rat alpha(2)M is generally kno wn as an acute-phase protein. Monoamine-activated forms of human alpha(2)M have been shown to inhibit various neuronal functions, but the effect of ra t alpha(1)M and acute-phase alpha(2)M on neurons is largely unknown, In thi s report, rat serotonin-activated alpha(2)M (5HT-alpha(2)M) has been demons trated to inhibit nerve growth factor (NGF)-promoted neurite extension in p heochromocytoma PC12 cells, and we investigated its possible mechanism of a ction including its effect on NGF-promoted signal transduction and gene exp ression in these cells. Especially in the absence of NGF, 5HT-alpha(2)M was found to bind to TrkA (the high-affinity receptor for NGF) much better tha n normal alpha(2)M (N-alpha(2)M). 5HT-alpha(2)M dose-dependently inhibited NGF-promoted autophosphorylation of TrkA, and decreased the expression of t wo immediate-early genes (NGFI-A, and c-jun) and two delayed-response genes (SCG10 and transin) which are associated with neurite outgrowth in PC12 ce lls. The unmodified N-alpha(2)M, on the other hand, exhibited very little o r no inhibitory effects on neurite extension, Trk phosphorylation, or expre ssion of these genes. The results of this study taken together suggest that monoamine-activated acute-phase rat alpha(2)M appears to inhibit neurite o utgrowth in PC12 cells possibly via its direct binding to TrkA and subseque nt blocking of TrkA-mediated signal transduction and gene expression. (C) 1 999 Wiley-Liss, Inc.