Premium
Serotonin‐activated α 2 ‐macroglobulin inhibits neurite outgrowth and survival of embryonic sensory and cerebral cortical neurons
Author(s) -
Liebl D. J.,
Koo P. H.
Publication year - 1993
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.490350207
Subject(s) - neurite , nerve growth factor , embryonic stem cell , serotonin , 5 ht receptor , neuroscience , chemistry , sensory system , cholinergic , microbiology and biotechnology , receptor , biology , medicine , endocrinology , biochemistry , in vitro , gene
Methylamine‐modified alpha‐2‐macroglobulin (MA‐α 2 M) has been recently shown to inhibit the biological activity of β‐nerve growth factor (NGF) in promoting neurite outgrowth by embryonic dorsal root ganglia in culture (Koo PH, Liebl DJ, J Neurosci Res 31:678–692, 1992). The objectives of this study are to determine whether α 2 M can also be modified by larger aromatic biogenic amines such as 5‐hydroxytryptamine (5HT; serotonin), the nature of interaction between NGF and 5HT‐modified alpha‐2‐M (5HT‐α 2 M), and the effect of 5HT‐α 2 M on the neurite extension and the growth of embryonic sensory and cholinergic neurons in 2 disparate animal species (chicken and rats). This study demonstrates that each mole of α 2 M can combine with 15.2 ± 1.8 moles of 5HT, in which up to 4.5 ± 0.4 moles may be covalently bonded. As determined by gel filtration and polyacrylamide gel electrophoresis studies, both 5HT‐α 2 M and normal α 2 M combine noncovalently with NGF, but 5HT‐α 2 M by comparison can combine with NGF somewhat more effectively. In contrast to normal α 2 M, 5HT‐α 2 M at concentrations greater than about 0.17 μM exerts a dose‐dependent inhibition on the NGF‐stimulated neurite outgrowth by embryonic dorsal root ganglia and dissociated cells in culture, and the inhibitory effect can be overcome by higher NGF concentrations. Both 5HT‐α 2 M and MA‐α 2 M at 1.0 μM inhibit neurite extension by embryonic rat cerebral cortical cells and seriously damage these cells in culture. Such neurite‐inhibitory activity, however, can only be partially blocked by extraneously added NGF alone. Normal α 2 M (at 1.0 μM) and 5HT (at 188 μM), on the other hand, under the identical conditions produce very little or no effect on the normal cellular and axonal growth of these cells. We conclude that α 2 M can potentially interact with nucleophilic monoamines, including neurotransmitters, to form inhibitory complexes which may inhibit/regulate NGF‐promoted neurite outgrowth and neuronal survival. In addition, higher concentrations of such complexes can seriously damage certain CNS neurons which do not depend solely on NGF for survival. © 1993 Wiley‐Liss, Inc.