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.