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Role of PKCα in linking MAP kinase to caspase‐3 in 5‐HT1A receptor mediated signalling
Author(s) -
Banerjee P.,
Adayev T.,
Sondhi R.,
Sobocki T.
Publication year - 2002
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 - 10.1046/j.1471-4159.81.s1.19_9.x
Subject(s) - microbiology and biotechnology , protein kinase c , mapk/erk pathway , kinase , agonist , chemistry , staurosporine , signal transduction , biology , receptor , biochemistry
Activation of caspases is a key step in initiation and execution of neuronal apoptosis following injury. Our earlier studies showed that the 5‐HT1A agonist (8‐OH‐DPAT) stimulates a PI‐3K‐independent mode of inhibition of caspase‐3. This results in an inhibition of anoxia‐induced apoptosis in the hippocampal neuron‐derived HN2‐5 cells through the extracellular signal‐regulated kinases (ERK1/2). Moreover, 5‐HT1A agonist treatment also blocks caspase‐3 activation in an ERK‐dependent manner during hydrogen peroxide mediated oxidative stress. This protective ERK activation involves Ca/Calmodulin (CaM) dependent endocytosis, since Fluphenazine, W‐7 (Ca/CaM inhibitors) and Monodansylcadaverine (an endocytosis inhibitor) effectively block the 8‐OH‐DPAT‐triggered ERK1/2 phosphorylation. A focal adhesion kinase (e.g. Pyk2) participates in this signal transduction pathway, since 8‐OH‐DPAT–mediated ERK1/2 activation is blocked in the presence of Cytochalasin D (a focal adhesion kinase inhibitor). Both a general inhibitor of PKCs (GFX) and a selective inhibitor of the calcium‐sensitive PKCs (Gö6976) reversed agonist‐induced suppresion of caspase‐3 activity, although GFX has no effect on the 5‐HT1A‐R‐mediated activation of ERK1/2. PKCα, but not PKCβ, immunoprecipitated from 8‐OH‐DPAT‐treated cells showed ERK1/2‐dependent stimulation, indicating the involvement of the PKCα isozyme. Transient expression of kinase‐negative PKCα in HN2‐5 cells caused elimination of the agonist‐evoked caspase‐3 inhibition, confirming that PKCα links the 5‐HT1A‐R‐MAPK pathway to the inhibition of caspase‐3. A study of this 5‐HT1A‐R‐mediated signalling cascade in other neuronal cells will demonstrate the generality of this novel pathway.