Nav1.8

Source: Wikipedia, the free encyclopedia.
(Redirected from
SCN10A
)
SCN10A
Identifiers
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000185313

ENSMUSG00000034533

UniProt

Q9Y5Y9

Q6QIY3

RefSeq (mRNA)

NM_001293306
NM_001293307
NM_006514

NM_001205321
NM_009134

RefSeq (protein)

NP_001280235
NP_001280236
NP_006505

NP_001192250
NP_033160

Location (UCSC)Chr 3: 38.7 – 38.82 MbChr 9: 119.44 – 119.55 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Nav1.8 is a

sodium ion channel subtype that in humans is encoded by the SCN10A gene.[5][6][7][8]

Nav1.8-containing channels are

sensory neurons called C-fibres, and is involved in nociception.[9][10] C-fibres can be activated by noxious thermal or mechanical stimuli and thus can carry pain
messages.

The specific location of Nav1.8 in sensory neurons of the DRG may make it a key therapeutic target for the development of new analgesics[11] and the treatment of chronic pain.[12]

Function

Voltage-gated sodium ion channels (VGSC) are essential in producing and propagating

nociceptors (damage-sensing neurons). Nav1.7, Nav1.8 and Nav1.9 are found in the DRG and help mediate chronic inflammatory pain.[13] Nav1.8 is an α-type channel subunit consisting of four homologous domains, each with six transmembrane regions, of which one is a voltage sensor.

Alpha subunit shown with four homologous domains each with six transmembrane spanning regions. The N-terminal and C-terminal are intracellular. Phosphorylation sites are shown for protein kinase A
Structure of Nav1.8, an α-type subunit with four homologous domains, each with six transmembrane regions. Each domain has a voltage sensor (purple). The 'P' represents the phosphorylation sites of Protein kinase A; N and C indicate the amino and carboxy termini of the protein chain. This image has been adapted from 'The trafficking of Nav1.8'[12]

knockout mice studies have shown that the channel is associated with inflammatory and neuropathic pain.[9][17][18] Moreover, Nav1.8 plays a crucial role in cold pain.[19] Reducing the temperature from 30 °C to 10 °C slows the activation of VGSCs and hence decreases the current. However, Nav1.8 is cold-resistant and is able to generate action potentials in the cold to carry information from nociceptors to the central nervous system (CNS). Furthermore, Nav1.8-null mice failed to produce action potentials, indicating that Nav1.8 is essential to the perception of pain in cold temperatures.[19]

Although the early studies on the biophysics of NaV1.8 channels were carried out in rodent channels, more recent studies have examined the properties of human NaV1.8 channels. Notably, human NaV1.8 channels exhibit an inactivation voltage-dependence that is even more depolarized than that in rodents, and it also exhibits a larger persistent current.[20] Thus, the influence of human NaV1.8 channels on firing of sensory neurons may be even larger than that of rodent NaV1.8 channels.

Gain-of-function mutations of NaV1.8, identified in patients with painful peripheral neuropathies, have been found to make DRG neurons hyper excitable, and thus are causes of pain.[21][22] Although NaV1.8 is not normally expressed within the cerebellum, its expression is up-regulated in cerebellar Purkinje cells in animal models of MS (Multiple Sclerosis), and in human MS.[23] The presence of NaV1.8 channels within these cerebellar neurons, where it is not normally present, increases their excitability and alters their firing pattern in vitro,[24] and in rodents with experimental autoimmune encephalomyelitis, a model of MS.[25] At a behavioral level, the ectopic expression of NaV1.8 within cerebellar Purkinje neurons has been shown to impair motor performance in a transgenic model.[26]

Clinical significance

Pain signalling pathways

Nociceptors are different from other sensory neurons in that they have a low activating threshold and consequently increase their response to constant stimuli. Therefore, nociceptors are easily sensitised by agents such as bradykinin and nerve growth factor, which are released at the site of tissue injury, ultimately causing changes to ion channel conductance. VGSCs have been shown to increase in density after nerve injury.[27] Therefore, VGSCs can be modulated by many different hyperalgesic agents that are released after nerve injury. Further examples include prostaglandin E2 (PGE2), serotonin and adenosine, which all act to increase the current through Nav1.8.[28]

Prostaglandins such as PGE2 can sensitise nociceptors to thermal, chemical and mechanical stimuli and increase the excitability of DRG sensory neurons. This occurs because PGE2 modulates the trafficking of Nav1.8 by binding to G-protein-coupled EP2 receptor, which in turn activates protein kinase A.[29][30] Protein kinase A phosphorylates Nav1.8 at intracellular sites, resulting in increased sodium ion currents. Evidence for a link between PGE2 and hyperalgesia comes from an antisense deoxynucleotide knockdown of Nav1.8 in the DRG of rats.[31] Another modulator of Nav1.8 is the ε isoform of PKC. This isoform is activated by the inflammatory mediator bradykinin and phosphorylates Nav1.8, causing an increase in sodium current in the sensory neurons, which promotes mechanical hyperalgesia.[32]

Brugada syndrome

Mutations in SCN10A are associated with

Brugada syndrome.[33][34][35]

Membrane trafficking

Nerve growth factor levels in inflamed or injured tissues are increased creating an increased sensitivity to pain (hyperalgesia).

plasma membrane. This contributes to the hyperexcitability of sensory neurons during pain.[37] p11-null nociceptive sensory neurons in mice, created using the Cre-loxP recombinase system, show a decrease in Nav1.8 expression at the plasma membrane.[38]
Therefore, disrupting the interactions between p11 and Nav1.8 may be a good therapeutic target for lowering pain.

In

lipid rafts along DRG fibers both in vitro and in vivo.[39] Lipid rafts organise the cell membrane, which includes trafficking and localising ion channels. Removal of lipid rafts in the membrane using MβCD, which depletes cholesterol from the plasma membrane, leads to a shift of Nav1.8 to a non-raft portion of the membrane, causing reduced action potential firing and propagation.[39]

Painful peripheral neuropathies

Painful

algorithms
, and yielded two gain-of-function mutations in SCN10A in three patients. Both mutations cause increased excitability in DRG sensory neurons and hence contribute to pain, but the mechanism by which they do so is not understood.

References

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034533 – Ensembl, May 2017
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  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Further reading

External links