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Activation of the histaminergic H 3 receptor induces phosphorylation of the Akt/GSK‐3β pathway in cultured cortical neurons and protects against neurotoxic insults
Author(s) -
Mariottini Chiara,
Scartabelli Tania,
Bongers Gerold,
Arrigucci Silvia,
Nosi Daniele,
Leurs Rob,
Chiarugi Alberto,
Blandina Patrizio,
PellegriniGiampietro Domenico E.,
Beatrice Passani Maria
Publication year - 2009
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.1471-4159.2009.06249.x
Subject(s) - protein kinase b , phosphorylation , biology , microbiology and biotechnology , kinase , signal transduction , mapk/erk pathway , histaminergic , pi3k/akt/mtor pathway , receptor , medicine , endocrinology , biochemistry
Stimulation of histamine H 3 receptors (H 3 R) activates G i/o ‐proteins that inhibit adenylyl cyclase and triggers MAPK and phospholipase A 2 . In a previous study, we showed that H 3 R‐mediated phosphorylation of Akt at Ser473 occurs in primary cultures of rat cortical neurons, but neither the downstream targets nor the function of such activation were explored. In this report we address these questions. Western blotting experiments showed that H 3 R‐mediated activation of Akt in cultured rat cortical neurons was inhibited by LY 294004 and U0126, suggesting that it depends on phosphoinositide‐3‐kinase and mitogen‐activated protein kinase kinase. H 3 R activation phosphorylated, hence inactivated, the Akt downstream effector glycogen synthase kinase‐3β, increased the expression of the antiapoptotic protein Bcl‐2 and protected cultured rat and mouse cortical neurons from neurotoxic insults in a dose‐dependent manner. All these effects were inhibited by the H 3 R antagonist inverse/agonist thioperamide. Mouse cortical cells expressed H 3 R as revealed by immunostaining experiments, and stimulation of H 3 R phoshorylated Akt and decreased caspase 3 activity. Hence, we uncovered a yet unexplored action of the H 3 R that may help understand the impact of H 3 R signaling in the CNS.