| A fundamental question in signal transduction is how multifunctional signaling molecules can achieve signal specificity. I have characterized how localization of substrates can regulate CaMKII phosphorylation. Unlike soluble substrates, membrane-restricted substrates require co-targeting of CaMKII for phosphorylation. In the postsynaptic density, intricate substrate scaffolding allows selective phosphorylation tuned to calcium entry through NMDA receptors. Furthermore, CaMKII can distinguish between substrates that are binding partners: PSD95 and Stargazin are phosphorylated while glutamate receptor subunits GluR1 and NR2B are not. These results demonstrate remarkable specificity to CaMKII substrate phosphorylation at excitatory synapses. |
