Activation of the histaminergic H3 receptor induces phosphorylation of the Akt/GSK-3 beta pathway in cultured cortical neurons and protects against neurotoxic insults

Stimulation of histamine H3 receptors (H3R) activates Gi/o-proteins that inhibit adenylyl cyclase and triggers MAPK and phospholipase A2. In a previous study, we showed that H3R-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 H3R-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. H3R 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 H3R antagonist inverse/agonist thioperamide. Mouse cortical cells expressed H3R as revealed by immunostaining experiments, and stimulation of H3R phoshorylated Akt and decreased caspase 3 activity. Hence, we uncovered a yet unexplored action of the H3R that may help understand the impact of H3R signaling in the CNS.