Nav1.7

Nav1.7 is a is_associated_with::sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of is_associated_with::neurons, the nociceptive (pain) neurons at is_associated_with::dorsal root ganglion (DRG) and is_associated_with::trigeminal ganglion, and is_associated_with::sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.

Function
Nav1.7 is a voltage-gated sodium channel and plays a critical role in the generation and conduction of is_associated_with::action potentials and is thus important for electrical signaling by most excitable cells. Nav1.7 is present at the endings of pain-sensing nerves, the is_associated_with::nociceptors, close to region where the impulse is initiated. Stimulation of the nociceptor nerve endings produces "generator potentials", which is small changes in the voltage across the neuronal membranes. The Nav1.7 channel amplifies these membrane depolarizations, and when the membrane potential difference reaches a specific threshold, the neuron fires. In sensory neurons, multiple voltage-dependent sodium currents can be differentiated by their voltage dependence and by sensitivity to the voltage-gated sodium-channel blocker is_associated_with::tetrodotoxin. The Nav1.7 channel produces a rapidly activating and inactivating current which is sensitive to level of is_associated_with::tetrodotoxin. Nav1.7 is important in early phases of neuronal is_associated_with::electrogenesis. Nav1.7 is described by slow transition of the channel into an inactive state when it is depolarized, even to a minor degree. This property that allows these channels to remain available for activation with even small or slowly developing is_associated_with::depolarizations. Stimulation of the nociceptor nerve endings produces "generator potentials", which is small changes in the voltage across the neuronal membranes. This brings neurons to certain voltage that stimulate Nav1.8, which has a more depolarized activation threshold that produces most of the transmembrane current responsible for the depolarizing phase of action potentials.

Animal studies
The critical role of Nav1.7 in is_associated_with::nociception and is_associated_with::pain was originally shown using is_associated_with::Cre-Lox recombination tissue specific knockout mice. These is_associated_with::transgenic mice specifically lack Nav1.7 in Nav1.8 positive nociceptors and showed reduced behavioural responses, specifically to acute mechanical and inflammatory pain assays. At the same time, behavioural responses to acute thermal and is_associated_with::neuropathic pain assays remained intact. However, the expression of Nav1.7 is not restricted to Nav1.8 positive DRG neurons. Further work examining the behavioural response of two other transgenic mouse strains; one lacking Nav1.7 in all DRG neurons and the another lacking Nav1.7 in all DRG neurons as well as all sympathetic neurons, has revealed distinct sets of modality specific peripheral neurons. Therefore Nav1.7 expressed in Nav1.8 positive DRG neurons is critical for normal responses to acute mechanical and inflammatory pain assays. Whilst Nav1.7 expressed in Nav1.8 negative DRG neurons is critical for normal responses to acute thermal pain assays. Finally, Nav1.7 expressed in sympathetic neurons is critical for normal behavioural responses to neuropathic pain assays.

Primary erythromelalgia
Mutation in Nav1.7 may result in primary is_associated_with::erythromelalgia (PE), an autosomal dominant, inherited disorder which is characterized by attacks or episodes of symmetrical burning is_associated_with::pain of the feet, lower legs, and sometimes hands, elevated skin temperature of affected areas, and reddened extremities. The mutation causes excessive channel activity which suggests that Nav1.7 sets the gain on pain signaling in humans. It was observed that a is_associated_with::missense mutation in the SCN9A gene affected conserved residues in the pore-forming α subunit of the Nav1.7 channel. Many studies have found a dozen SCN9A mutations in multiple families as causing erythromelagia. All of the observed is_associated_with::erythromelalgia mutations that are observed are missense mutations that change important and highly conserved amino acid residues of the Nav1.7 protein. The majority of mutations that cause PE are located in cytoplasmic linkers of the Nav1.7 channel, however some mutations are present in is_associated_with::transmembrane domains of the channel. The PE mutations cause a hyperpolarizing shift in the voltage dependence of channel activation, which allows the channel to be activated by smaller than normal depolarizations, thus enhancing the activity of Nav1.7. Moreover, the majority of the PE mutations also slow deactivation, thus keeping the channel open longer once it is activated. In addition, in response to a slow, depolarizing stimulus, most mutant channels will generate a larger than normal sodium current. Each of these alterations in activation and deactivation can contribute to the hyperexcitability of pain-signaling DRG neurons expressing these mutant channels, thus causing extreme sensitivity to pain is_associated_with::hyperalgesia. While the expression of PE Nav1.7 mutations produces hyperexcitability in DRG neurons, studies on cultured rat in is_associated_with::sympathetic ganglion neurons indicate that expression of these same PE mutations results in reduction of excitability of these cells. This occurs because Nav1.8 channels, which are selectively expressed in addition to Nav1.7 in DRG neurons, are not present within sympathetic ganglion neurons. Thus lack of Nav1.7 results in inactivation of the sodium channels results in reduced excitability. Thus physiological interaction of Nav1.7 and Nav1.8 can explain the reason that PE presents with pain due to hyperexcitability of is_associated_with::nociceptors and with sympathetic dysfunction that is most likely due to hypoexcitability of sympathetic ganglion neurons. Recent studies have associated a defect in SCN9A with is_associated_with::congenital insensitivity to pain.

Paroxysmal extreme pain disorder
is_associated_with::Paroxysmal extreme pain disorder (PEPD) is another rare, extreme pain disorder. Like primary erythromelalgia, PEPD is similarly the result of a gain-of-function mutation in the gene encoding the Nav1.7 channel.

Congenital insensitivity to pain
Individuals with is_associated_with::congenital insensitivity to pain have painless injuries beginning in infancy but otherwise normal sensory responses upon examination. Patients frequently have bruises and cuts, and are often only diagnosed because of limping or lack of use of a limb. Individuals have been reported to be able to walk over burning coals and to insert knives and drive spikes through their arms. It has been observed that the insensitivity to pain does not appear to be due to axonal degeneration.

A mutation that caused loss of Nav1.7 function has been detected in three consanguineous families from northern Pakistan. All mutation observed were is_associated_with::nonsense mutation with majority of affected patients having homozygous mutation in the SCN9A gene. Their observation linked loss of Nav1.7 function with incapability to experience pain. The result was in contrast with the genetic basis of primary is_associated_with::erythromelalgia in which the disorder results from gain-of-function mutations.

Clinical analgesics
is_associated_with::Local anesthetics such as is_associated_with::lidocaine mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels. Nav1.7, as well as Nav1.3, Nav1.8, and Nav1.9, are the specific channels that have been implicated in pain signaling. Thus, the blockade of these specific channels is likely to underlie the analgesia of local anesthetics. In addition, inhibition of these channels is also likely responsible for the analgesic efficacy of certain is_associated_with::anticonvulsants, as well as, in part, that of certain is_associated_with::tricyclic antidepressants, and of is_associated_with::mexiletine.

Future prospects
As the Nav1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia, there has been immense interest in developing selective Nav1.7 channel blockers as potential novel analgesics. Since Nav1.7 is not present in heart tissue or the central nervous system, selective blockers of Nav1.7 – unlike non-selective blockers such as local anesthetics – could be safely used systemically for pain relief. Moreover, selective Nav1.7 blockers may prove to be far more effective analgesics – and without side effects – relative to current pharmacotherapies.

A number of selective Nav1.7 (and/or Nav1.8) blockers are in clinical development, including is_associated_with::CNV1014802, is_associated_with::TV-45070 (formerly XEN402), is_associated_with::PF-05089771, is_associated_with::PF-04531083, is_associated_with::DSP-2230, is_associated_with::AZD-3161, is_associated_with::NKTR-171, is_associated_with::GDC-0276, and is_associated_with::RG7893 (formerly GDC-0287). is_associated_with::Ralfinamide (formerly NW-1029, FCE-26742A, and PNU-0154339E) is a multimodal, non-selective Nav channel blocker which is under development for the treatment of pain.