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Glia‐conditioned medium induces de novo synthesis of tyrosine hydroxylase and increases dopamine cell survival by differential signaling pathways
Author(s) -
de Bernardo S.,
Canals S.,
Casarejos M. J.,
RodriguezMartin E.,
Mena M. A.
Publication year - 2003
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.10704
Subject(s) - protein kinase c , protein kinase a , staurosporine , microbiology and biotechnology , wortmannin , biology , mapk/erk pathway , signal transduction , tyrosine hydroxylase , kinase , ask1 , receptor tyrosine kinase , mitogen activated protein kinase kinase , protein kinase b , endocrinology , dopamine
The mesencephalic astroglia‐conditioned medium (GCM) greatly increases dopamine (DA) phenotype expression, and it also protects from spontaneous and toxin‐induced cell death in midbrain cultures. In this study, we have investigated the signaling pathways implicated in those effects. Genistein at 5 μM, an inhibitor of tyrosine kinase receptors, and KT‐5720, a protein kinase A inhibitor, blocked the GCM‐induced effects on DA phenotype expression and DA cell survival but did not abolish the increased astrocytic (glial fibrillary acidic protein‐positive; GFAP + ) processes. We analyzed the role of phosphatidylinositol‐3 kinase (PI‐3K) on TH induction and cell survival, with the PI‐3K inhibitors LY‐294002 and wortmannin, and the role of the phosphorylation of mitogen‐activated protein kinase (MAPK) with PD‐98059, a p‐ERK1/2 MAPK inhibitor. LY‐294002 at 20–30 μM blocked the GCM‐induced effects on TH expression and DA cell survival but did not abolish the increased astrocytic processes. PD‐98059 at 20 and 40 μM blocked the GCM‐induced effects on DA phenotype, cell survival, and GFAP expression. However, staurosporine at 10 nM, a protein kinase C inhibitor, only blocked the protective effects induced by GCM on midbrain cell apoptosis. The data presented herein show that tyrosine kinase receptors, cAMP‐dependent protein kinase, PI‐3K, and MAPK signaling pathways are implicated in de novo synthesis of TH + cells induced by GCM as well as in DA cell apoptosis and that these effects are unrelated to increased GFAP expression. PKC inhibitors only abolished the GCM‐induced effects on midbrain neuronal survival, suggesting that signaling pathways for DA phenotype expression and survival may be independent. © 2003 Wiley‐Liss, Inc.