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= Nav1.9 =

Voltage-gated sodium channel, or alpha subunit, type XI, also known as SCN11A or Nav1.9, is a voltage-gated sodium ion channel protein which is encoded by the SCN11A gene on chromosome 3 in humans. Like Nav1.7 and Nav1.8, Nav1.9 plays a role in pain perception. This channel is largely expressed in small-diameter nociceptors of the dorsal root ganglion and trigeminal ganglion neurons, but is also found in intrinsic myenteric neurons.

Function
Voltage-gated sodium channels are membrane protein complexes that play a fundamental role in the rising phase of the action potential in most excitable cells. Alpha subunits, such as SCN11A, mediate voltage-dependent gating and conductance, while auxiliary beta subunits regulate the kinetic properties of the channel and facilitate membrane localization of the complex. Aberrant expression patterns or mutations of alpha subunits underlie a number of disorders. Each alpha subunit consists of 4 domains connected by 3 intracellular loops; each domain consists of 6 transmembrane segments and intra- and extracellular linkers. The 4th transmembrane segment of each domain is the voltage-sensing region of the channel. Following depolarization of the cell, voltage-gated sodium channels become inactivated through a change in conformation in which the 4th segments in each domain move into the pore region in response to the highly positive voltage expressed at the peak of the action potential. This effectively blocks the Na+ pore and prevents further influx of Na+, therefore preventing further depolarization. Similarly, when the cell reaches its minimum (most negative) voltage during hyperpolarization, the 4th segments respond by moving outward, thus reopening the pore and allowing Na+ to flow into the cell.

Nav1.9 is known to play a role in nociception, having been linked to the perception of inflammatory, neuropathic, and cold-related pain. It does this primarily through its ability to lower the threshold potential of the neuron, allowing for an increase in action potential firing that leads to hyperexcitability of the neuron and increased pain perception. Because of this role in altering the threshold potential, Nav1.9 is considered a threshold channel.

Though most sodium channels are blocked by tetrodotoxin, Nav1.9 is tetrodotoxin-resistant due to the presence of serine on an extracellular linker that plays a role in the selectivity of the pore for Na+. This property is found in similar channels, namely Nav1.8, and has been associated with slower channel kinetics than the tetrodotoxin-sensitive sodium channels. In Nav1.9, this is mostly associated with the slower speed at which channel inactivation occurs.

Gain-of-Function Mutations in Humans
There are currently many known gain-of-function mutations in the human SCN11A gene that are associated with various pain abnormalities. The majority of these mutations lead to the experience of episodic pain, mainly in the joints of the extremities. In some of these mutants, the pain symptoms began in early childhood and diminished somewhat with age, but some of the mutants were asymptomatic until later in adulthood. Many of these conditions are also accompanied by gastrointestinal disturbances such as constipation and diarrhea. Additionally, one gain-of-function mutation on SCN11A has been linked with a congenital inability to experience pain.

Animal Models of Pain
Both Nav1.8 and Nav1.9 have been shown to play a role in bone cancer associated pain using a rat model of bone cancer. The dorsal root ganglion of lumbar 4-5 of rats with bone cancer were shown to have up-regulation of Nav1.8 and Nav1.9 mRNA expression as well as an increase in total number of these alpha subunits. This research suggests that these tetrodotoxin-resistant voltage gated sodium channels are involved in the development and maintenance of bone cancer pain.

The role of Nav1.9 in chronic inflammatory joint pain has been demonstrated in rat models of chronic inflammatory knee pain. Expression of Nav1.9 in the afferent neurons of the dorsal root ganglion was found to be elevated as many as four weeks after the onset of the inflammatory pain. These results indicated that this alpha subunit plays some role in the maintenance of chronic inflammatory pain.

Pain Relief Implications
The role of Nav1.9 in inflammatory and neuropathic pain has made it a protein of interest for pain relief research. It is thought that a drug that targets Nav1.9 could be used to decrease pain effectively while avoiding the many side effects associated with other high-strength analgesics. Research on the use of topical menthol as a pain relief treatment has shown that menthol blocks both Nav1.8 and Nav1.9 channels in the dorsal root ganglion. Menthol showed an ability to inhibit action potentials by dampening the Na+ channel activity without affecting normal neural activity in the affected area. Nav1.9 has also been proposed as a site of treatment for oxaliplatin's side effects of cold-associated pain.