Insulin induces phosphorylation of the AMPA receptor subunit GluR1, reversed by ZIP, and over-expression of Protein Kinase M zeta, reversed by amyloid beta

The insulin receptor (IR) in the brain plays a crucial role in regulating synaptic plasticity and cognitive function. Phosphorylation of the GluR1 subunit of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors at serine 831—a modification critical for long-term potentiation and learning/memory—is mediated by calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC). Recent findings have identified the novel protein kinase M zeta (PKMζ) as a key regulator of AG-1024 synaptic plasticity, potentially modulating AMPA receptor function.
In this study, we demonstrate that insulin promotes phosphorylation of GluR1 at serine 831 and induces overexpression of PKMζ. These effects were reversed by pre-treatment with either the IR inhibitor AG1024 (3-Bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile) or a PKMζ-specific inhibitor (PKCζ pseudosubstrate inhibitor), which restored GluR1 phosphorylation to baseline levels.
Furthermore, oligomeric amyloid beta (Aβ) peptides, known to disrupt IR signaling, were found to reduce insulin-induced PKMζ overexpression and MAPK/Erk1/2 phosphorylation when applied to neuronal cultures pre-treated with insulin. These signaling pathways are essential for synaptic function and memory formation.
Collectively, these results identify a novel intracellular signaling cascade mediated by insulin and implicate impaired insulin signaling—induced by Aβ accumulation—as a contributing factor to insulin resistance in Alzheimer’s disease.