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The C‐terminal domain of the heavy chain of tetanus toxin rescues cerebellar granule neurones from apoptotic death: involvement of phosphatidylinositol 3‐kinase and mitogen‐activated protein kinase pathways
Author(s) -
ChaïbOukadour Imane,
Gil Carles,
Aguilera José
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02586.x
Subject(s) - microbiology and biotechnology , wortmannin , kinase , mapk/erk pathway , biology , protein kinase a , protein kinase b , mapk cascade , chemistry , biochemistry , phosphatidylinositol , signal transduction
When cultured cerebellar granule neurones are transferred from a medium containing high extracellular potassium concentration ([K + ] e ) (25 m m ) to one with lower [K + ] e (5 m m ), caspase‐3 activity is induced and cells die apoptotically. In contrast, if cells in non‐depolarizing conditions are treated with brain‐derived neurotrophic factor (BDNF), caspase‐3 activity, chromatin condensation and cell death are markedly diminished. In this study, we show that the C‐terminal domain of the tetanus toxin heavy‐chain (Hc‐TeTx) is able to produce the same neuroprotective effect, as assessed by reduction of tetrazolium salts and by chromatin condensation. Hc‐TeTx‐conferred neuroprotection appears to depend on phosphatidylinositol 3‐kinase (PI3K) and mitogen‐activated protein kinase kinase, as is demonstrated by the selective inhibitors Wortmannin and PD98059, respectively. Hc‐TeTx also induces phosphorylation of the tyrosine kinase BDNF receptor, activation of p21Ras in its GTP‐bound form, and phosphorylation of the cascade including extracellular‐signal‐regulated kinases‐1/2 (ERK‐1/2), p90 ribosomal S6 kinase (p90rsk) and CREB (cAMP‐response‐element‐binding protein). On the other hand, activation of the Akt pathway is also detected, as well as inhibition of the active form of caspase‐3. These results point to an implication of both PI3K‐ and ERK‐dependent pathways in the promotion of cerebellar granule cell survival by Hc‐TeTx.