Neuronal architecture in health and disease

Neurons are a diverse group of cells responsible for receiving and transmitting information throughout the brain. Transmembrane proteins, known as ion channels, initiate and maintain the electrical signals, which flow down neuronal axons.

The intrinsic axonal excitability and function are largely dependent on the expression and localisation of voltage-gated sodium (Nav) and potassium (Kv) ion channels, which can be located at the Axon Initial Segment (AIS) and the Nodes of Ranvier. Failure of these channels to be properly localised and propagate the axon potential can lead to neuronal pathology.

Thus, identifying regulatory mechanisms of ion channel expression and localisation is essential for understanding pathological phenotypes. In this context, scientists on the EU-funded CHANNEL TARGETING project investigated molecular and cellular determinants governing the appropriate targeting and assembly of Nav and Kv1 in axons.

Their findings revealed that dynamic phosphorylation by the caseine kinase (CK2) and cyclin-dependent kinases (CDK), regulates Nav and Kv1 localisation, respectively. They found that not only CK2-mediated phosphorylation participates in Nav1 clustering in vivo, but CK2 specific localisation at the AIS also depends on Nav1 expression. As for Kv1 channels, CDK reversibly phosphorylates their auxiliary subunits (Kv2) influencing their binding with microtubule-associated protein EB1. Consequently, this allows for their proper axonal membrane insertion.

Taken together, the CHANNEL TARGETING study enhanced our knowledge about the molecular mechanisms regulating axonal ion channel expression and clustering. This re-emphasises how such dynamic regulations can play a crucial role in calibrating neuronal excitability in normal and pathological conditions.