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Nouvelle traduction : mécanismes cellulaires et (...)

The axonal initial segment (IS), located at the boundary between the soma and the axon is characterised notably by the segregation of voltage-gated sodium channels (Nav), ankyrin G and bIV spectrin. In cultured hippocampal neurons, Nav1.2 is segregated and anchored in the IS. To obtain new insights into the mechanisms involved in Nav1.2 compartmentalization, our objectives were to identify : (1) the molecular signals and partners implicated (2) the pathway(s) of targeting in the IS. By using a strategy based on the expression of chimera proteins, we showed that the large the cytoplasmic loop linking the transmembrane domains II and III of Nav1.2 (Nav1.2 II-III ) contains two independent and distinct motifs : (1) a motif of targeting and anchoring in the IS, conserved in all the Nav1 and interacting with ankyrin G (2) an endocytosis motif. To identify the partners involved in Nav1.2 segregation in the IS, we used the yeast-two hybrid system, Nav1.2 II-III as bait. Schwannomin Interacting Protein 1 (SCHIP-1) was identified and its interaction with Nav1.2 II-III confirmed in vitro. SCHIP-1 is enriched in the IS of cultured hippocampal neurons and in vivo in the IS and the nodes of Ranvier. Its function is still unknown. The analysis of the traffic of a reporter protein segregated in the IS led us to propose the following model : (1) the protein initially inserted in the somato-dendritic plasma membrane (2) reach the axonal domain by diffusion (3) in the IS, the protein is trapped by interaction with ankyrin G (4) its segregation in the IS is achieved by selective endocytosis in the somato-dendritic domain and in the distal part of the axon.

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