Cell-type-dependent molecular composition of the axon initial segment
Open accessAbstract
The exact site of initiation and shape of action potentials vary among different neuronal types. The reason for this variability is largely unknown, but the subunit composition, density and distribution of voltage-gated sodium (Nav) and potassium (Kv) channels within the axon initial segment (AIS) are likely to play a key role. Here, we asked how heterogeneous are the density and distribution of Nav and Kv channels within the AISs of a variety of excitatory and inhibitory neurons. Most of the studied cell types expressed a high density of Nav1.6, Kv1.1, and Kv1.2 subunits in their AIS, but the Nav1.1 subunit could only be detected in GABAergic interneurons. A proximo-distal gradient in the density of these subunits was observed within the AIS of certain nerve cells but not in others. For example, a gradual increase of the Nav1.6 subunit was observed in cortical layer 2/3 and hippocampal CA1 pyramidal cell (PC) AISs, whereas its density was rather uniform in layer 5 PC AISs. The Nav1.1 subunit was distributed evenly along the AIS of short-axon cells of the main olfactory bulb but was restricted to the proximal part of the AIS in cortical and cerebellar interneurons. Our results reveal a cell type-dependent expression of sodium and potassium channel subunits with varying densities along the proximo-distal axis of the AISs. This precise arrangement is likely to contribute to the diversity of firing properties observed among central neurons.
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At least in cortical regions, NaV1.1 channels affected in Dravet are more commonly expressed in inhibitory neurons, and NaV1.1 loss of function may have opposing effects on brain networks compared with NaV1.2 loss of function in excitatory neurons.
“When considering such treatments, it is critical to remember that, at least in cortical regions, NaV1.1 channels affected in Dravet are more commonly expressed in inhibitory neurons [59], and that loss of function with NaV1.1 may have opposing effects on brain networks compared to NaV1.2 loss of function in excitatory neurons.”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [59]
Both Kv1.1 and Kv1.2 are highly enriched at the axon initial segment where they colocalize with the voltage-gated sodium channel Nav1.6.
“Both Kv1.1 and Kv1.2 are highly enriched at the axon initial segment where they colocalize with the voltage-gated sodium channel Nav1.6 (415, 695).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [695]
Compared with the axon initial segments of principal cells, Kv1.1 and Kv1.2 are expressed at a much higher density.
“When compared with the axon initial segments of principal cells, Kv1.1 and Kv1.2 are expressed at a much higher density (695), suggesting that they may play a role in establishing an increased threshold for action potential initiation in PV-containing cells.”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [695]
The molecular identities of Na+ channels in interneurons suggest that at least in PVBCs the vast majority of Na+ channels are formed by Nav1.1 and Nav1.6 subunits with a lesser contribution from Nav1.2, Nav1.4, and Nav1.7.
“The molecular identities of Na+ channels in interneurons suggest that at least in PVBCs the vast majority of Na+ channels are formed by Nav1.1 and Nav1.6 subunits with a lesser contribution from Nav1.2, Nav1.4, and Nav1.7 (502, 695, 857, 852).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [695]
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“1 channels affected in Dravet are more commonly expressed in inhibitory neurons [59], and that loss of function with NaV1.”
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- Authors
- Lorincz, A., & Nusser, Z.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-12-31
- Volume
- 28
- Issue
- 53
- Pages
- 14329-14340
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2628579
- OpenAlex
- W2048111738
- Cited by
- 382
- References
- 47
- Citations by year
- 2026: 7 · 2025: 26 · 2024: 16 · 2023: 23 · 2022: 14 · 2021: 21 · 2020: 26 · 2019: 21 · 2018: 25 · 2017: 20 · 2016: 24 · 2015: 25 · 2014: 30 · 2013: 25 · 2012: 26
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (070213)
- European Commission (LSHM-CT-2005-019055)
- Magyar Tudományos Akadémia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- axon initial segment, voltage-gated sodium channels, voltage-gated potassium channels, Nav1.6, Nav1.1, Kv1.1, Kv1.2, proximo-distal gradient, action potential generation, excitatory and inhibitory neurons, GABAergic interneurons, pyramidal neurons, cortical interneurons, olfactory bulb interneurons, cerebellar interneurons, neuronal firing properties
- MeSH terms
- Animals, Axons, Brain, Ion Channels, Male, Nerve Tissue Proteins, Neurons, Sodium Channels, Rats, Wistar, Mice, Knockout, Mice, Rats, Kv1.1 Potassium Channel, Kv1.2 Potassium Channel, NAV1.1 Voltage-Gated Sodium Channel, NAV1.6 Voltage-Gated Sodium Channel
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