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 a-amino-3-hydroxy- 5-methylisoxazole-4-propionic acid (AMPA) receptors GluR1 subunit at Serine 831 is regulated by calcium-calmodulindependent 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 (PKMf) 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 PKMf; pre-treatment with either the IR inhibitor 3-Bromo-5-tbutyl- 4-hydroxy-benzylidenemalonitrile (AG1024) or PKMf inhibitor protein kinase C zeta pseudo-substrate inhibitor returned the phosphorylation value of GluR1 to control level. Amyloid beta (Ab) peptide in the form of oligomers interferes with IR signaling. Pre-treating neuronal cultures with Ab following incubation with insulin, we found a reduction of insulin-dependent PKMf 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 Ab.