Insulin receptor (IR) in the brain plays a role in synaptic plasticity and cognitive functions. Phosphorylation of Î±-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 (PKMÎ¶) 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 PKMÎ¶; pre-treatment with either the IR inhibitor 3-Bromo-5-tbutyl-4-hydroxy-benzylidenemalonitrile (AG1024) or PKMÎ¶ inhibitor protein kinase C zeta pseudo-substrate inhibitor returned the phosphorylation value of GluR1 to control level. Amyloid beta (AÎ²) peptide in the form of oligomers interferes with IR signaling. Pre-treating neuronal cultures with AÎ² following incubation with insulin, we found a reduction of insulin-dependent PKMÎ¶ 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 AÎ².
|Titolo:||Insulin induces phosphorylation of the AMPA receptor subunit GluR1, reversed by ZIP, and over-expression of protein kinase M zeta, reversed by amyloid beta|
DOMENICI, LUCIANO (Corresponding)
|Data di pubblicazione:||2014|
|Appare nelle tipologie:||1.1 Articolo in rivista|