Dynamic compartmentalization of the voltage-gated sodium channels in axons

• Published in: Biology of the Cell 2003-10, Vol.95 (7), p.437-445
• Main Authors: Garrido, Juan José, Fernandes, Fanny, Moussif, Anissa, Fache, Marie-Pierre, Giraud, Pierre, Dargent, Bénédicte
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Animals; Axon; Axons - chemistry; Cell Compartmentation; Clustering; Endocytosis; Intercellular Signaling Peptides and Proteins - analysis; NAV1.2 Voltage-Gated Sodium Channel; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - chemistry; Neuronal polarity; Rats; Sodium channel; Sodium Channels - analysis; Sodium Channels - chemistry; Targeting
• ISSN: 0248-4900; 1768-322X
• DOI: 10.1016/S0248-4900(03)00091-1

One of the major physiological roles of the neuronal voltage-gated sodium channel is to generate action potentials at the axon hillock/initial segment and to ensure propagation along myelinated or unmyelinated fibers to nerve terminal. These processes require a precise distribution of sodium channels accumulated at high density in discrete subdomains of the nerve membrane. In neurons, information relevant to ion channel trafficking and compartmentalization into sub-domains of the plasma membrane is far from being elucidated. Besides, whereas information on dendritic targeting is beginning to emerge, less is known about the mechanisms leading to the polarized distribution of proteins in axon. To obtain a better understanding of how neurons selectively target sodium channels to discrete subdomains of the nerve, we addressed the question as to whether any of the large intracellular regions of Nav 1.2 contain axonal sorting and/or clustering signals. We first obtained evidence showing that addition of the cytoplasmic carboxy-terminal region of Na v1.2 restricted the distribution of a dendritic-axonal reporter protein to axons of hippocampal neurons. The analysis of mutants revealed that a di-leucine-based motif mediates chimera compartmentalization in axons and its elimination in soma and dendrites by endocytosis. The analysis of the others generated chimeras showed that the determinant conferring sodium channel clustering at the axonal initial segment is contained within the cytoplasmic loop connecting domains II-III of Na v1.2. Expression of a soluble Na v1.2 II-III linker protein led to the disorganization of endogenous sodium channels. The motif was sufficient to redirect a somatodendritic potassium channel to the axonal initial segment, a process involving association with ankyrin G. Thus, it is conceivable that concerted action of the two determinants is required for sodium channel compartmentalization in axons.