Insulin induces phosphorylation of the AMPA receptor subunit GluR1, reversed by ZIP, and over-expression of Protein Kinase M zeta, reversed by amyloid beta.
Insulin receptor (IR) in the brain plays a role in synaptic plasticity and cognitive functions. Phosphorylation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors GluR1 subunit at Serine 831 is regulated by calcium-calmodulin-dependent protein kinase II and protein kinase C that underlie long-term potentiation and learning/memory. Recent studies have shown that the novel Protein Kinase M zeta (PKMζ) underlies synaptic plasticity and may regulate AMPAr. In this study, we show that insulin induces phosphorylation of Serine 831 GluR1 subunit of AMPAr and induces over-expression of PKMζ; pre-treatment with either the IR inhibitor 3-Bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile (AG1024) or PKMζ inhibitor protein kinase C zeta pseudo-substrate inhibitor returned the phosphorylation value of GluR1 to control level. Amyloid beta (Aβ) peptide in the form of oligomers interferes with IR signaling. Pre-treating neuronal cultures with Aβ following incubation with insulin, we found a reduction of insulin-dependent PKMζ over-expression and MAPK/Erk (1/2) phosphorylation, i.e., signaling pathways involved in synaptic plasticity and learning/memory. These results indicate a new intracellular insulin signaling pathway, and, additionally, that insulin resistance in Alzheimer's disease is a response to the production and accumulation of Aβ.
['Adzovic|Linda|L|', 'Domenici|Luciano|L|']
D016229:Amyloid beta-Peptides D000818:Animals D001921:Brain D002478:Cells, Cultured D004305:Dose-Response Relationship, Drug D005260:Female D005786:Gene Expression Regulation D007004:Hypoglycemic Agents D007328:Insulin D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009474:Neurons D010446:Peptide Fragments D010766:Phosphorylation D011493:Protein Kinase C D018091:Receptors, AMPA D012097:Repressor Proteins D012694:Serine D020032:Tyrphostins
Insulin AMPA ZIP PKMζ Aβ Alzheimer