p600 stabilizes microtubules to prevent the aggregation of CaMKIIα during photoconductive stimulation

The large microtubule-associated/Ca2+-signalling protein p600 (also known as UBR4) is required for hippocampal neuronal survival upon Ca2+ dyshomeostasis induced by glutamate treatment. During this process, p600 prevents aggregation of the Ca2+/calmodulin-dependent kinase II alpha (CaMKII alpha), a proxy of neuronal death, via direct binding to calmodulin in a microtubuleindependent manner. Using photoconductive stimulation coupled with live imaging of single neurons, we identified a distinct mechanism of prevention of CaMKII alpha aggregation by p600. Upon direct depolarization, CaMKII alpha translocates to microtubules. In the absence of p600, this translocation is interrupted in favour of a sustained self-aggregation that is prevented by the microtubule-stabilizing drug paclitaxel. Thus, during photoconductive stimulation, p600 prevents the aggregation of CaMKII alpha by stabilizing microtubules. The effectiveness of this stabilization for preventing CaMKII alpha aggregation during direct depolarization but not during glutamate treatment suggests a model wherein p600 has two modes of action depending on the source of cytosolic Ca2+.