NaG
Description: Voltage-gated Sodium channel type 2 Gene: scn7a Alias: Nav2, Nav2.1, Nav2.3, NaX, NaC, Nav1.10, SCL11
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]
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]
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 |
Human NaG is made of 1682 amino acids and has a molecular weight of 193 Kda.
Isoforms
There has been no significant research on the effect of PTMs on NaG
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
Methodology for AlphaFold size prediction and disclaimer are available here
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]
There has been no single channel unitary conductance recordings for NaG nor have any kinetic models been generated
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]
To date, the subcellular location of NaG has not been identified in the CNS.
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]
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).
Sun J
et al.
Genomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases.
Nat Commun, 2019Jul18, 10 (3190).
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).
Potts JF
et al.
A glial-specific voltage-sensitive Na channel gene maps close to clustered genes for neuronal isoforms on mouse chromosome 2.
Biochem. Biophys. Res. Commun.,
1993
Nov
30
, 197 (100-4).
Noda M
et al.
The Na(x) Channel: What It Is and What It Does.
Neuroscientist,
2015
Aug
, 21 (399-412).
Watanabe E
et al.
NaX sodium channel is expressed in non-myelinating Schwann cells and alveolar type II cells in mice.
Neurosci. Lett.,
2002
Sep
13
, 330 (109-13).
Poulsen PC
et al.
Quantitative proteomics characterization of acutely isolated primary adult rat cardiomyocytes and fibroblasts.
J Mol Cell Cardiol, 2020Jun, 143 (63-70).
Hiyama TY
et al.
The subfornical organ is the primary locus of sodium-level sensing by Na(x) sodium channels for the control of salt-intake behavior.
J. Neurosci.,
2004
Oct
20
, 24 (9276-81).
Poiraud E
et al.
The Na-G ion channel is transcribed from a single promoter controlled by distinct neuron- and Schwann cell-specific DNA elements.
J. Neurochem.,
1999
Dec
, 73 (2575-85).
Zhang B
et al.
The association between the polymorphisms in a sodium channel gene SCN7A and essential hypertension: a case-control study in the Northern Han Chinese.
Ann. Hum. Genet.,
2015
Jan
, 79 (28-36).
Hou C
et al.
Knockout of sodium channel Nax delays re-epithelializathion of splinted murine excisional wounds.
Wound Repair Regen, 2021Mar, 29 (306-315).
Treccani G
et al.
Early life adversity targets the transcriptional signature of hippocampal NG2+ glia and affects voltage gated sodium (Nav) channels properties.
Neurobiol Stress, 2021Nov, 15 (100338).
Yan Y
et al.
Comprehensive Analysis to Identify the Encoded Gens of Sodium Channels as a Prognostic Biomarker in Hepatocellular Carcinoma.
Front Genet, 2021, 12 (802067).
Yuan P
et al.
Genomic analyses reveal SCN7A is associated with the prognosis of esophageal squamous cell carcinoma.
Esophagus, 2022Apr, 19 (303-315).
Ke CB
et al.
Enhanced SCN7A/Nax expression contributes to bone cancer pain by increasing excitability of neurons in dorsal root ganglion.
Neuroscience,
2012
Dec
27
, 227 (80-9).
Liu Q
et al.
Transcriptional Alterations of Mouse Trigeminal Ganglion Neurons Following Orofacial Inflammation Revealed by Single-Cell Analysis.
Front Cell Neurosci, 2022, 16 (885569).
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).
Contributors: Katherine Johnston
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