p600 is a large protein that is enriched in the brain and expressed in neurons. Previous work has shown a diversity of functions for p600 in several different organisms and cell types. Following a report that p600 associates with the Ca2+ sensor calmodulin (CaM), we hypothesized that p600 was acting as a Ca2+ signalling protein in hippocampal neurons, a population of cells which is susceptible to Ca2+-induced death. We found that in the presence of Ca2+, p600 associates with CaM and the ubiquitous Ca2+/CaM-dependent protein kinase IIα (CaMKIIα). This interaction is mediated by a direct and atypical interaction between residues 4086-4111 on p600 and CaM. Using a peptide based on this sequence to specifically block the p600/CaM interaction, we determined that this interaction is required for the survival of hippocampal neurons. This survival was found to be dependent on the Ca2+-influx through the N-methyl-D-aspartate (NMDA) receptor during ambient culture activity. We next assessed the regulation of CaMKIIα in order to determine the mechanism by which p600 promotes neuronal survival. Under pathological conditions, namely elevated intracellular Ca2+ concentrations and decreased intracellular pH, CaMKIIα undergoes a rapid aggregation. We therefore used this aggregation as a marker for pathological intracellular conditions. Predictably, treatment with glutamate and glycine to induce Ca2+ entry caused CaMKIIα aggregation, and depletion of p600 by RNAi sensitized neurons to this effect. Within each neuron, the amount of CaMKIIα aggregation was found to correlate significantly with the amount of fragmentation of the endoplasmic reticulum (ER), suggesting that p600 controls ER morphology. Using a battery of inhibitors, the aggregation of CaMKIIα was found to depend primarily on Ca2+ influx through NMDA receptors, on ER Ca2+ stores by way of inositol-3-phosphate receptors, and somewhat on influx through L-type voltage-dependent channels. The microtubule-stabilizing compound paclitaxel decreased the likelihood of CaMKIIα aggregation in directly-depolarized neurons, but not those given glutamate/glycine treatment, indicating that p600 regulates microtubule stability in response to certain sources of Ca2+ entry. In sum, these data show that p600 promotes the survival of hippocampal neurons through a novel role as a Ca2+-signalling protein.