The Akt/GSK-3β axis as a new signaling pathway of the histamine H3 receptor

Drugs targeting the histamine H3 receptor (H3R) are suggested to be beneficial for the treatment of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. The H3R activates Gi/o-proteins to inhibit adenylyl cyclase activity and modulates phospholipase A2 and MAPK activity. Herein we show that, in transfected SK-N-MC cells, the H3R modulates the activity of the Akt/Glycogen synthase kinase 3β (GSK-3β) axis both in a constitutive and agonist-dependent fashion. H3R stimulation with the H3R agonist immepip induces the phosphorylation of both Ser473 and Thr308 on Akt, a serine/threonine kinase that is important for neuronal development and function. The H3R-mediated activation of Akt can be inhibited by the H3R inverse agonist thioperamide, and by Wortmannin, LY294002 and PTX, suggesting the observed Akt activation occurs via a Gi/o-mediated activation of phosphoinositide-3-kinase. H3R activation also results in the phosphorylation of Ser9 on GSK-3β, which acts downstream of Akt and has a prominent role in brain function. In addition, we show the H3R-mediated phosphorylation of Akt at Ser473 to occur in primary rat cortical neurons and in rat brain slices. The discovery of this signaling property of the H3R adds new understanding to the roles of histamine and the H3R in brain function and pathology.