CaMKII as a Multimodal Signalling Hub in Neural Connectivity and Vulnerability

Calcium/calmodulin-dependent protein kinase II (CaMKII) is one of the most abundant and versatile signalling molecules in the brain, uniquely positioned to convert transient signals into durable structural and functional changes. Classical models cast CaMKII as a Ca2+/calmodulin-activated kinase that, once phosphorylated, persists autonomously to encode synaptic memory. Recent work has reframed this view, revealing CaMKII as a state and context-dependent signalling hub that integrates catalytic activity with structural and scaffolding functions. Its activity and persistence are shaped by partner protein interactions, higher-order assembly, redox and metabolic modifications, and confinement within nanoscale domains. Isoform and splice diversity further distribute CaMKII into specialised pools across dendritic spines, growth cones, axons, and nuclei, enabling it to regulate synaptic plasticity, axon growth, and long-term neuronal stability through both enzymatic and non-enzymatic mechanisms. These actions are dynamically sculpted by opposing phosphatases, including PP1, PP2A, and calcineurin, which do not simply terminate signalling but bias the kinase toward kinetically stabilised functional configurations with distinct catalytic and structural outputs. Here we outline a conceptual multistate regulatory framework in which CaMKII can occupy basal, catalytically active, and structurally stabilised functional regimes, rather than operating as a simple bistable switch. In this framework, these regimes are defined by differences in signalling persistence and molecular interactions rather than by formally demonstrated stable attractors, providing a functional model for understanding how CaMKII integrates spatially restricted Ca2+ signals with phosphatase control. Disruption of regulated transitions between these regimes through altered phosphatase balance, aberrant spatial confinement, or pathological modification can shift CaMKII signalling into inappropriate compartments or timescales, contributing to neurodevelopmental, psychiatric, and neurodegenerative disorders. This review highlights recent advances in activation mechanisms, isoform-specific organisation, phosphatase control, and disease biology, positioning CaMKII as a hybrid structural-catalytic integrator whose state-dependent regulation offers new opportunities for precision therapeutic intervention.