title: Insulin induces phosphorylation of the AMPA receptor subunit GluR1, reversed by ZIP, and over-expression of Protein Kinase M zeta, reversed by amyloid beta.
abstract: 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.
authors.affiliation: Neuroscience Institute, CNR, Pisa, Italy; Department of Psychology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Adzovic
authors.forename: Luciano
authors.initials: L
authors.lastname: Domenici
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism*; D012097:Repressor Proteins / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D000099221:Protein Kinase C zeta
chemical_list: D016229:Amyloid beta-Peptides; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D011493:Protein Kinase C; D018091:Receptors, AMPA; D012097:Repressor Proteins; D012694:Serine; D020032:Tyrphostins; D000099221:Protein Kinase C zeta; C075222:amyloid beta-protein (1-42); C447031:tyrphostin AG 1024
keywords: AMPA; Alzheimer; Aβ; Insulin; PKMζ; ZIP