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Nav1.7

sodium channel, voltage-gated, type IX, alpha
Synonyms: nav1.7 scn9a. Symbol: Scn9a

Introductions


SCN9A (also known as PN1; ETHA; NENA; FEB3B; NE-NA; GEFSP7; Nav1.7) encodes the tetrodotoxin sensitive channel Nav1.7, a voltage-gated sodium channel, type IX, alpha subunit which plays a significant role in nociception signaling. Nav1.7 regulates sensory neuron excitability and contributes to several sensory modalities. Mutations in SCN9A have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder.

http://www.ncbi.nlm.nih.gov/gene/6335 [1419]

Genes


Scn9a : sodium channel, voltage-gated, type IX, alpha

RGD ID Chromosome Position Species
69368 3 48438725-48518893 Rat
737152 2 66318137-66473009 Mouse
737151 2 167051695-167232497 Human

Transcripts


Acc No Sequence Length Source
NM_133289 NCBI
NM_018852 NCBI
NM_002977 NCBI

Ontologies


Accession Name Definition Evidence
GO:0001518 voltage-gated sodium channel complex A sodium channel in a cell membrane whose opening is governed by the membrane potential. IDA
GO:0016020 membrane Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins. IEA
GO:0016021 integral to membrane Penetrating at least one phospholipid bilayer of a membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. When used to describe a protein, indicates that all or part of the peptide sequence is embedded in the membrane. IEA

Interactions


The nerve-growth-factor-induced increase in peak voltage geated sodium channel current density in strongly metastatic Mat-LyLu cell (model of rat prostate cancer) was suppressed by both the pan-trk antagonist K252a, and the protein kinase A inhibitor KT5720. Nerve-growth-factor did not affect the Nav1.7 mRNA level, but the total VGSC a-subunit protein level was upregulated. [215]

Tetrodotoxin

Nav1.7 is TTX sensitive (non selective) [1376]

Proteins


Structures


Each α subunit - hence also Nav1.7 - is composed of four homologous domains (DI-DIV), with each domain consisting of six transmembrane segments (S1–S6), with S4 acting as a voltage-sensor and S5 and S6 lining the pore [815]. Structural modellings approach of Nav1.7 have identified an aromatic residue within the cytoplasm-proximal portion of each of the pore-lining S6 helices that were predicted to form a hydrophobic ring at the cytoplasmic end of the pore that stabilizes the channel’s pre-open state. This element is predicted to raise the energy barrier for the movement of S6, which is necessary to open the channel’s pore, thus stabilizing the closed or pre-open state of the channel [1419][1420].

Distributions


NaV1.7 is uniformly distributed in the somata of in both large and small diameter DRG neurons and along the identified Aβ-fibres and C fibres, being expressed at high levels in nociceptive neurons. NaV1.7 is present peripherally within free nerve endings in the epidermis and centrally within superficial lamina of the dorsal horn in the spinal cord [850][1419].

Expressions


NaV1.7 expression is detected in [1419], [847], [848]:
• Somatosensory and sympathetic ganglion
• Myenteric neurons
• Olfactory sensory neurons (OSNs)
• Visceral sensory neurons
• Smooth myocytes (in the plasmalemma) [1425]
Measurable NaV1.7 levels have not been detected in other regions of the CNS in humans but in rodent it has been detected in the hypothalamus and in the pituitary gland [1423].
NaV1.7 expression has also been detected within non-excitable cells, including: the adrenal glands (only in rodents) [1423] prostate and breast tumour cells, human erythroid progenitor cells, immune cells [1419] and in the strongly metastatic Dunning rat PCa Mat-LyLu cell line, VGSC/Nav1.7 a-subunit mRNA was upregulated over 1,000-fold, compared to the isogenic weakly metastatic AT-2 cells [835], [847], [848].

Functionals


Activated MAPK to regulate the expression of Nav1.7 in diabetic neuropathy [1421] and in human neuromas [1422].

Primary erythromelalgia has been linked to mutations in SCN9A, the gene that encodes voltage-gated sodium channel NaV1.7 [851], [214].

Channelopathies

Mutations in Nav1.7 have been identified in patients several human disorders (for further information see Table 3 of [1422]):
* Anosmia [846]
* Inherited erythromelalgia (IEM) [1424]
* Paroxysmal extreme pain disorder (PEPD)[1424]
* Channelophaty-associated insensitivity to pain (CIP) [1424]

Functional voltage gated sodium channel expression is considered "necessary and sufficient" for potentiation of prostate cancer cell invasiveness [853] and it is also involved in the pain mechanisms of Parkinson Disease [1425].

Mouse models:
- Nav1.7 Conditional KO (burn injury) [1426]
- Nav1.7/Nav1.8 double KO [1427]
- Nav1.7/Nav1.8 double KO (infammatory pain) [1428]
- Nav1.7 null [1428]. This mutation in lethal in rodents but not in humans. The lethality of the Nav1.7 knockout mice is due to failure to feed, possibly resulting from dysfunctions of central, autonomic or enteric sensory neurons because of a distinct expression of Nav1.7 in rodent brain and in endocrine glands [1423].

Kinetics


Based on its biophysical properties, Nav1.7 is poised to amplify generator potentials in neurons expressing it, including nociceptors, and to act as a threshold channel for firing action potentials and setting the gain in pain-signaling neurons [1419]. NaV1.7 produces a rapidly activating and inactivating [213] and is characterized by slow closed-state inactivation, allowing the channel to produce a substantial ramp current in response to small, slow depolarizations[849]. NaV1.7 is considered to be a threshold channel because of its ability to boost subthreshold stimuli increases the probability of neurons reaching their threshold for firing action potentials. In DRG neurons, Nav1.7 produces resurgent currents triggered by repolarization following a strong depolarization [1419].

Models


References


[213 : 12843211]
[214 : 18171466]
[215 : 17149708]
[216 : 18803825]
[847 : 10784102]
[848 : 12527742]
[849 : 9822722]
[815 : 10798388]
[851 : 16278094]
[1419 : 23232607]
[1420 : 20367448]
[1421 : 18579738]
[1422 : 20130174]
[850 : 9037087]
[1415 : 16020462]
[846 : 21441906]
[1424 : 21490662]
[853 : 11494332]
[1425 : 22473870]
[1426 : 22875917]
[1427 : 16111501]
[1428 : 15314237]
[1423 : 17597096]

Credits