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 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-3beta, 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.
Mariottini
Chiara
C
Dipartimento di Scienze Fisiologiche, Universitá di Firenze, Firenze, Italy.
Scartabelli
Tania
T
Bongers
Gerold
G
Arrigucci
Silvia
S
Nosi
Daniele
D
Leurs
Rob
R
Chiarugi
Alberto
A
Blandina
Patrizio
P
Pellegrini-Giampietro
Domenico E
DE
Passani
Maria Beatrice
MB
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D017442:Histamine Agonists / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D017442:Histamine Agonists; D018696:Neuroprotective Agents; D018100:Receptors, Histamine H3; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3