CHANNEL TARGETING

Identification of the dynamic mechanisms regulating the targeting and clustering of sodium and potassium channels in neurons

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 Obiettivo del progetto (Objective)

'The electrical excitability is a fundamental property of neurons. Diversity in intrinsic neuronal excitability is generated by the variable expression, subcellular localization, and function of a complex repertoire of ion channels. Dynamic regulation of intrinsic excitability can further alter the behavior of neurons and confer plasticity to neuronal signaling. Aberrant expression, localization, and function of ion channels can result in channel-based pathophysiologies. One of the challenging questions is to understand how neurons regulate the expression and localization of ion channels. The Axon Inital Segment (AIS) and the nodes of Ranvier are key sub-compartments that generate and conduct the action potentials along the axon. The voltage-dependent sodium (Nav) and potassium (Kv) channels are critically concentrated at the AIS and nodes of Ranvier to ensure proper axon potential propagation. Despite the central role of these channels in excitability, the molecular and cellular determinants governing their appropriate targeting and membrane organization are just beginning to emerge. An intricate assembly of adhesion molecules and cytoskeletal scaffold proteins hold Nav and Kv channels in place. However, how such a complex is dynamically regulated is still largely unknown. We recently identified two new processes based on phosphorylation of Nav and Kv complexes by two kinases, casein kinase 2 (CK2) and cyclin-dependant kinase (Cdks). The phosphorylation/dephosphorylation modifications of these channels modify indeed their localization at the AIS. Here, I propose to analyze, using a multidisciplinary approach, the respective role of CK2 and Cdks signaling pathways on dynamic targeting/assembly of Nav1 and Kv1 channels at the AIS and in the node of Ranvier. The end-results of this proposal should provide new insights into the mechanisms involved in the dynamic regulation of excitability and opens new paths to better understand defects leading to neuronal dysfunction.'

Introduzione (Teaser)

European researchers investigated the structure of neurons in normal and abnormal conditions. Their work focused on the localisation and modification of ion channels, which are vital for proper signal transmission.

Descrizione progetto (Article)

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.