Functional specialization of the axon initial segment by isoform-specific sodium channel targeting

Boiko, Tatiana; Van Wart, Audra; Caldwell, John H.; Levinson, S. Rock; Trimmer, James S.; Matthews, Gary

doi:10.1523/jneurosci.23-06-02306.2003

Cited by 311Ion channel regulation and functionIon Channels and ReceptorsIon Transport and Channel Regulation

Functional specialization of the axon initial segment by isoform-specific sodium channel targeting

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Boiko, Tatiana, Van Wart, Audra, Caldwell, John H., Levinson, S. Rock, Trimmer, James S., Matthews, Gary·2003·The Journal of Neuroscience

DOI 10.1523/jneurosci.23-06-02306.2003PMC PMC6742039

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Abstract

Voltage-dependent sodium channels cluster at high density at axon initial segments, where propagating action potentials are thought to arise, and at nodes of Ranvier. Here, we show that the sodium channel Na v 1.6 is precisely localized at initial segments of retinal ganglion cells (RGCs), whereas a different isoform, Na v 1.2, is found in the neighboring unmyelinated axon. During development, initial segments first expressed Na v 1.2, and Na v 1.6 appeared later, approximately in parallel with the onset of repetitive RGC firing. In Shiverer mice, Na v 1.6 localization at the initial segment was unaffected, although Na v 1.6 expression was severely disrupted in the aberrantly myelinated optic nerve. Targeting or retention of Na v 1.6 requires molecular interactions that normally occur only at initial segments and nodes of Ranvier. Expression at nodes but not initial segments exhibits an additional requirement for intact myelination. Because of their high density at the initial segment, Na v 1.6 channels may be crucial in determining neuronal firing properties.

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Early in development, NaV1.2 is the only sodium channel isoform expressed in the axon initial segment, the site of action potential initiation.
“Early on, NaV1.2 is the only sodium channel isoform expressed in the axon initial segment (AIS) [3,16,17], an axonal subcompartment located proximal to the soma that is the site of action potential initiation [18].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [16]
The Discussion states that before NaV1.6 appeared, only NaV1.2 was observed at initial segments. The study examined developing retinal ganglion cells, so it does not establish that this is true of axon initial segments generally. The action-potential-initiation clause has a separate citation and is not attributed to this paper here. (LLM, conf=0.83)
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Authors: Boiko, T., Van Wart, A., Caldwell, J. H., Levinson, S. R., Trimmer, J. S., & Matthews, G.
Affiliations: University of Colorado Denver (US)
Stony Brook University (US)
ORCID: Caldwell, John H.
Levinson, S. Rock
Trimmer, James S.
Matthews, Gary
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2003-03-15
Volume: 23
Issue: 6
Pages: 2306-2313
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.23-06-02306.2003
PMC: PMC6742039
OpenAlex: W2148218137
Cited by: 311
References: 33
Citations by year: 2026: 6 · 2025: 11 · 2024: 14 · 2023: 9 · 2022: 10 · 2021: 19 · 2020: 15 · 2019: 20 · 2018: 13 · 2017: 11 · 2016: 13 · 2015: 10 · 2014: 10 · 2013: 11 · 2012: 10
FWCI: 5.40
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5p01ns034375-05, NS34375)
National Eye Institute (EY-03821, R01EY003821)
National Institute of Neurological Disorders and Stroke (NS-34375, NS34383, NS 26505, R01NS034383, R01NS026505, R37NS034383)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords: axon initial segment, sodium channel isoforms, Nav1.6, Nav1.2, retinal ganglion cells, nodes of Ranvier, action potential generation, shiverer mice, myelination, optic nerve, neuronal firing properties, channel localization
MeSH terms: Animals, Axons, Cell Differentiation, Fluorescent Antibody Technique, Immunohistochemistry, Mice, Neurologic Mutants, Myelin Sheath, Nerve Growth Factors, Nerve Tissue Proteins, Optic Nerve, Retina, Retinal Ganglion Cells, Sodium Channels, Cell Adhesion Molecules, Rats, Sprague-Dawley, Ankyrins, Protein Isoforms, Mice, Rats, NAV1.2 Voltage-Gated Sodium Channel

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Functional specialization of the axon initial segment by isoform-specific sodium channel targeting

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