Calcium‐calmodulin Dependent Protein Kinase II: An Unforgettable Story

According to the National Institutes of Health, 5.1 million Americans have Alzheimer's disease (AD), which affects memory and the ability to learn. In long‐term potentiation (LTP), a correlate of learning and memory, the number of receptors at the synapse increases. Calcium/calmodulin dependent protein kinase II (CaMKII), a large dodecameric enzyme comprising 1–2% of all proteins in the brain, is part of a signaling pathway implicated in LTP. In this pathway, Ca+2 binds calmodulin (CaM) and the Ca+2/CaM complex activates CaMKII, which then phosphorylates other proteins in the cell, like α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors. To investigate the role of CaMKII, the Cedarburg SMART (Students Modeling A Research Topic) Team used 3D printing technology to design a CamKII model, highlighting the catalytic, self‐association, and autoinhibitory domains. The Ca+2/CaM complex activates CaMKII by displacing a portion of the autoinhibitory domain that blocks the active site of the enzyme, exposing both the catalytic base and Thr286, the residue involved in autophosphorylation. When CaMKII phosphorylates AMPA receptors, their numbers increase in the post synaptic neuron and they are more sensitive to glutamate. Impaired LTP may lead to the cognitive decline seen in AD. Funded by a grant from NIH‐SEPA 1R25OD010505–01 from NIH‐CTSA UL1RR031973.