Channelpedia

NaG

Description: Voltage-gated Sodium channel type 2
Gene: scn7a
Alias: Nav2, Nav2.1, Nav2.3, NaX, NaC, Nav1.10, SCL11

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Introduction

NaG channel, sometimes referred to as NaX, NaC, Nav1.10 and also formerly known as SCL11 (in rats), Nav2.3 (in mice) and Nav2.1 (in humans), is encoded by the gene scn7a in humans, sometimes referred to as scn6a in rodents. [2273]. The channel is present in both the CNS and PNS.
NaG is classified as a subfamily of the voltage-gated sodium channels but it is not activated by the depolarisation of the membrane potential. Instead it is sensitive to extracellular concentrations of Na+ ions and plays a role in sodium homeostasis [2274]


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Gene

NaG is encoded by the gene scn7a and is located on chromosome 2 (2q24.3), in a gene cluster that includes scn1a (Nav1.1), scn2a (Nav1.2), scn3a (Nav1.3), and scn9a (Nav1.7). It is made up of made of 25 exons, 24 of which are coding and exon 1 being non-coding. However, in rodents, the encoding gene is sometimes referred to as scn6a. Phylogenetic analysis suggests that scn7a arose most recently as it is only present in eutherian mammals [2273]

Species NCBI gene ID Chromosome Position
Human 6332 2 90676
Mouse 20272 2 111484
Rat 64155 3 102467

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Transcript

Upon transcription, human scn7a generates a 7.5 kb mRNA [2275]

Species NCBI accession Length (nt)
Human NM_002976.4 7465
Mouse NM_009135.2 7333
Rat NM_001388508.1 6837

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Protein Isoforms

Human NaG is made of 1682 amino acids and has a molecular weight of 193 Kda.

Species Uniprot ID Length (aa)
Human Q01118 1682
Mouse
Rat P97706 1702

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform

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Post-Translational Modifications

There has been no significant research on the effect of PTMs on NaG

PTM
Position
Type

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Structure

Though the channel is made up of 4 domains, each with 6 transmembrane segments, the primary structure of NaG is markedly different than other voltage-gated sodium channels, particularly the voltage sensing and inactivations segments [2276]

The voltage sensing (transmembrane 4) regions of scn7a have lost several key basic amino acids, arginine and lysines, especially in domains II and IV. This results in a channel with aberrant voltage-gating functions. Furthermore, the IFM motif in the extracellular loop between domains III and IV has undergone a methionine to isoleucine substitution. Such modifications to this motif, critical for the proper fast inactivation of a VGSCs, causes a significant shift in inactivation [2273] [2220]

NaG predicted AlphaFold size

Species Area (Å2) Reference
Human 11206.53 source
Mouse
Rat no data source

Methodology for AlphaFold size prediction and disclaimer are available here


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Kinetics

To date, there has been no success in expressing a functional NaG alone in a heterologous expression system, suggesting the requirement of an as-yet unidentified partner [872] [879] [875]

However, in vivo, NaG current has been characterized as having a more negative onset of activation and slower gating kinetics than other Nav currents [2275] The reason behind this change in kinetics is probably due to NaG being a concentration-sensitive Na+ channel with a threshold of ~150 mM for extracellular Na+ concentration [2276]


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Biophysics

There has been no single channel unitary conductance recordings for NaG nor have any kinetic models been generated


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Expression and Distribution

NaG can be found in both the central nervous system (CNS) and peripheral nervous system (PNS).

NaG has been widely identified in the PNS in locations such as the lung, heart, intestine, bladder, kidney, skin, and tongue. Within these tissues, NaG is particularly present in a subset of Schwann cells within the peripheral nerve trunks but can also be found in myocytes and fibroblasts. [2277] [2278] [2279]

In the CNS, expression of NaG is mostly found in subpopulations of neurons in the thalamus, hippocampus, and cerebellum. More specifically, NaG expression is limited to sensory circumventricular organs (CVOs). The CVOs are midline structures, in which the blood-brain barrier (BBB) is missing, that harbour neuronal cells. Sensory CVOs include the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), both areas essential for the monitoring of hydromineral homeostasis. Within those areas, NaG is predominantly found in the glial cells (ependymal cells and astrocytes) [2276] [2280]


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CNS Sub-cellular Distribution

To date, the subcellular location of NaG has not been identified in the CNS.


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Function

Hydromineral homeostasis

Since NaG has lost most of its voltage-gated character and instead activates in a concentration-dependent manner to extracellular sodium ions, NaG plays an important role in the regulation of sodium homeostasis. Indeed, scn7a-deficient mice lose the normal preference for fresh water over saline water in dehydration experiments. However, wild-type behaviour is restored by introducing scn7a expression into the SFO using an adenoviral expression vector. [2274]

The mechanisms by which NaG then signal to the rest of the body to stop salt ingestion and hydrate requires a number of other regulatory proteins whose interaction with NaG can be found in the Interactions section

Channelopathies

Given NaG’s crucial role in proper ion homeostasis, deregulation of the channel results in a number of pathologies

Modifications to NaG have been shown to be the cause of:

  • Hypertension [2281]
  • Fibrosis in a number of tissues (renal, skin, liver, etc. )[2282] [2273]
  • Decreased wound healing, inflammation. [2273]

The root cause is thought to be the deregulation of the Na+ ion balance within the tissues as a consequence of aberrant NaG.

Mutations to snc7a or changes in NaG expression are also key biomarkers in a number of cancers including:

  • Lung Adenocarcinoma [2283]
  • Hepatocellular carcinoma [2284]
  • Esophageal squamous cell carcinoma [2285]
  • Brain metastases [2265]

In the context of cancer, enhanced expression of the NaG channel within distinct subpopulations of DRG neurons also contributes to cancer pain by increasing the excitability of these neurons. [2286] [2287]


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Interaction

Though relatively little research has been conducted on NaG, a few compounds that interact with the channel have been identified

NaG contains a PDZ binding motif in its C-terminus. Synapse-associated protein 97 (SAP97/DLG1) was shown to interact with this motif when co-expressed with NaG in the subfornical organ. Destruction of the binding motif or removal of SAP97 resulted in decreased cell surface expression of NaG, indicating that the protein is likely involved in the stabilization of protein trafficking to the plasma membrane. [2288]

[Na+] is known to be strictly controlled at 135 to 145 mM in the serum and cerebrospinal fluid (CSF) [2289]. However, as seen in Kinetics, NaG activates when the extracellular Na+ concentrations are at ~150 mM. The way NaG can still activate at physiological Na+ concentrations is through its interaction with a coexpressed protein, endothelin-3 (ET-3). ET-3 lowers the [Na+]o concentration dependency of Nax,which enables NaG to activate within physiological Na+ ranges. [2276]

NaG also interacts directly with Na+/K+-ATPases via its C-terminal region, resulting in sensitization of glial cells to Na+-induced uptake of glucose. This interaction plays a crucial role in the influx in glucose and the subsequent lactate release. The produced lactate acts as a gliotransmitter to stimulate γ-aminobutiric acid-containing inhibitory neurons (GABAergic neurons), that in turn, control salt-intake behaviour [2273][2276]


References

Widmark J et al. Differential evolution of voltage-gated sodium channels in tetrapods and teleost fishes.
Mol. Biol. Evol., 2011 Jan , 28 (859-71).

Dolivo D et al. The Nax (SCN7A) channel: an atypical regulator of tissue homeostasis and disease.
Cell Mol Life Sci, 2021Jul, 78 (5469-5488).

Hiyama TY et al. Na(x) channel involved in CNS sodium-level sensing.
Nat. Neurosci., 2002 Jun , 5 (511-2).

Noda M et al. The Na(x) Channel: What It Is and What It Does.
Neuroscientist, 2015 Aug , 21 (399-412).

Matsumoto M et al. SAP97 promotes the stability of Nax channels at the plasma membrane.
FEBS Lett., 2012 Nov 2 , 586 (3805-12).

Peruzzo M et al. Body fluids and salt metabolism - part II.
Ital J Pediatr, 2010Dec13, 36 (78).


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Credits

Contributors: Katherine Johnston

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/217/ , accessed on 2024 Dec 02