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Sodium channel, voltage gated, type X, alpha subunit also known as SCN10A or Nav1.8 is a protein which in humans is encoded by the SCN10A gene.[1] Nav1.8 is a sodium channel subunit.[2][3][4]

Nav1.8 is a tetrodotoxin (TTX)-resistant voltage-gated sodium ion channel. It is expressed specifically in the dorsal root ganglion (DRG), in unmyelinated, small-diameter sensory neurons called C-fibres and is involved in the pain pathway called nociception.[5][6] C-fibres can be activated by noxious thermal or mechanical stimuli and thus can carry pain messages. The discrete locations of Nav1.8 in sensory neurons of the DRG may be the key factor in therapeutic targets for the development of new analgesics[7] and to treat chronic pain.[8]

Function edit

Voltage-gated sodium ion channels (VGSC) are essential in producing and propagating action potentials. Tetrodotoxin, a toxin found in pufferfish is able to block some VGSCs and therefore is used to distinguish the different subtypes. There are three TTX-resistant VGSC: Nav1.5, Nav1.8 and Nav1.9. Nav1.8 and Nav1.9 are both expressed in nociceptors (damage-sensing neurons). It is known that Nav1.7, Nav1.8 and Nav1.9 are located in the DRG and play an important role in maintaining chronic inflammatory pain.[9]

Nav1.8 α-subunit consists of four homologous domains each with six transmembrane spanning regions of which one is a voltage sensor. Voltage clamp methods were used to show how action potentials in small diameter DRG cell bodies are shaped by TTX-resistant sodium channels. Nav1.8 contributes the most to sustaining the depolarising stage of the action potentials in nociceptive sensory neurons by activating quickly and remaining activated[10][11] after detecting a noxious stimuli.

Therefore, Nav1.8 is known to perform a key role in hyperalgesia and allodynia which are part of chronic pain.[12] Nav1.8 knockout mice studies have shown that the channel is associated with inflammatory and neuropathic pain.[5][13][14] Moreover, Nav1.8 plays a crucial role in cold pain.[15] Zimmermann et al. show that 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 therefore indicating Nav1.8 is essential in the notion of pain in cold temperatures.[15]

 
Structure of the α-subunit of Nav1.8 showing the four homologous domains each with six transmembrane regions. Each domain has a voltage sensor represented in this diagram by a purple region. The 'P' represents the phosphorylation sites of protein kinase A (PKA).[8]

Clinical significance edit

Pain signalling pathway edit

Nociceptors are different to 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 (NGF), 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.[16] Therefore, VGSCs can be modulated by many different hyperalgesic agents that are released after nerve injury and further examples include prostaglandin E2 (PGE2), serotonin (5-HT) and adenosine, which all act to increase the current through Nav1.8.[17]

Prostaglandins (e.g. PGE2) can sensitise nociceptors to thermal, chemical and mechanical stimuli and increase the excitability of DRG sensory neurons. This occurs due to PGE2 modulating the trafficking of Nav1.8 by binding to G-protein coupled EP2 receptor which in turn activates protein kinase A (PKA).[18] PGE2 modulates the trafficking of Nav1.8 by binding to G-protein coupled EP2 receptor which in turn activates protein kinase A (PKA).[19] PKA phosphorylates Nav1.8 at intracellular sites resulting in increased sodium ion currents. Evidence for PGE2 linking to hyperalgesia comes from an antisense deoxynucleotide knockdown of Nav1.8 in the DRG of rats.[20] Another modulator of Nav1.8 is the ε isoform of PKC (PKCε). PKCε is activated by inflammatory mediator bradykinin and phosphorylates Nav1.8 causing an increase in sodium current in the sensory neurons, which plays an important role is mechanical hyperalgesia.[21]

Membrane trafficking edit

Nerve growth factor (NGF) levels in inflamed or injured tissues are increased creating an increased sensitivity to pain (hyperalgesia).[22] The increased levels of NGF and tumour necrosis factor-α (TNF-α) causes the upregulation of Nav1.8 in sensory neurons via the accessory protein p11 (annexin II light chain). It has been shown using the yeast-two hybrid screening method that p11 binds to a 28 amino acid fragment of the N-terminal of Nav1.8 and promotes its translocation to the plasma membrane. This contributes to the hyperexcitability of sensory neurons during pain.[23] p11-null nociceptive sensory neurons in mice, created using the Cre-LoxP recombinase system, showed a decrease in Nav1.8 expression at the plasma membrane.[24] Therefore, disrupting the interactions between p11 and Nav1.8 may be a good therapeutic target to lower pain.

In myelinated fibres VGSCs are located at the nodes of Ranvier however, in unmyelinated fibres the exact location of VGSCs have not been found. Nav1.8 is located in unmyelinated fibres and has been found to be located in clusters associated with lipid rafts along DRG neurons both in vitro and in vivo.[25] 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 in the plasma membrane that is crucial for lipid rafts, leads to a shift of Nav1.8 to a non-raft portion of the membrane, causing reduced action potential firing and propagation.[25]

Painful peripheral neuropathies edit

Painful peripheral neuropathies or small-fibre neuropathies are disorders of unmyelinated nociceptive C-fibres causing neuropathic pain and in some cases there is no known cause.[26] Patients with these idiopathic neuropathies have been screened genetically to find mutations in the SCN9A gene encoding Nav1.7. A gain-of-function mutation in Nav1.7 located in the DRG sensory neurons was found in 30% of patients.[27] This gain-of-function mutation causes an increase in excitability (hyperexcitability) of DRG sensory neurons thus causing an increase in pain. Nav1.7 has therefore been shown to be linked to human pain however, Nav1.8 had only been associated to pain in animal studies until recently. A gain-of-function mutation was found in the Nav1.8 encoding SCN10A gene in patients with painful peripheral neuropathy.[28] Faber et al. used voltage clamp and current clamp methods along with predictive algorithms on 104 idiopathic patients who did not have the mutation in SCN9A. They found two gain-of-function mutations in SCN10A in three patients in which both mutations cause increased excitability in DRG sensory neurons and hence they contribute to pain but the mechanism in which they do so is not understood.

References edit

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  27. ^ Faber CG, Hoeijmakers GK, Ahn H, Cheng X, Han C, Choi J, Lauria G, Vanhoutte EK, Gerrits MM, Dib-Hajj S, Drenth JPH, Waxman SG & Merkies ISJ (2012). "Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy". Annals of Neurology. 71: 26–39. doi:10.1002/ana.22485.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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Further reading edit

External Links edit

The London Pain Consortium

Category:Ion channels

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