Sodium voltage-gated channel alpha subunit 9

Last updated

SCN9A
PDB 1byy EBI.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SCN9A , ETHA, FEB3B, GEFSP7, HSAN2D, NE-NA, NENA, Nav1.7, PN1, SFNP, sodium voltage-gated channel alpha subunit 9
External IDs OMIM: 603415; MGI: 107636; HomoloGene: 2237; GeneCards: SCN9A; OMA:SCN9A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6335

20274

Ensembl

ENSG00000169432

ENSMUSG00000075316

UniProt

Q15858

Q62205

RefSeq (mRNA)

NM_002977
NM_001365536

NM_001290674
NM_001290675
NM_018852

RefSeq (protein)

NP_002968
NP_001352465

NP_001277603
NP_001277604

Location (UCSC) Chr 2: 166.2 – 166.38 Mb Chr 2: 66.31 – 66.47 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Sodium voltage-gated channel alpha subunit 9 (also Nav1.7) is a sodium ion channel that, in humans, is encoded by the SCN9A gene. [5] [6] [7] It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at the dorsal root ganglion (DRG) and trigeminal ganglion; and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system. [8] [9]

Contents

Function

Structure of human voltage-gated sodium channel alpha subunit 9 in complex with auxiliary beta subunits, ProTx-II and tetrodotoxin (Y1755 down) from the RCSB PDB (6J8J). NaV 1.7 PDB 6j8j.png
Structure of human voltage-gated sodium channel alpha subunit 9 in complex with auxiliary beta subunits, ProTx-II and tetrodotoxin (Y1755 down) from the RCSB PDB (6J8J).

Sodium voltage-gated channel alpha subunit 9 plays a critical role in the generation and conduction of 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 nociceptors, close to the region where the impulse is initiated. Stimulation of the nociceptor nerve endings produces "generator potentials", which are 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 tetrodotoxin. The Nav1.7 channel produces a rapidly activating and inactivating current which is sensitive to the level of tetrodotoxin. [10] Nav1.7 is important in the early phases of neuronal electrogenesis. Nav1.7 activity consists of a slow transition of the channel into an inactive state when it is depolarized, even to a minor degree. [11] This property allows these channels to remain available for activation with even small or slowly developing depolarizations. Stimulation of the nociceptor nerve endings produces "generator potentials", small changes in the voltage across the neuronal membranes. [11] This brings neurons to a 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. [12]

Cell-Based Assays

Heteromultimeric ion channels such as Nav1.7 comprise multiple subunits including a pore forming subunits and accessory subunits. Creation of laboratory cells that comprise multiple subunits is challenging. Fluorogenic signaling probes and flow cytometry have been used to create laboratory cells that comprise heteromultimetic Nav1.7 including at least two of its accessory subunits. [13]

Clinical significance

Animal studies

The critical role of Nav1.7 in nociception and pain was originally shown using Cre-Lox recombination tissue specific knockout mice. These 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 neuropathic pain assays remained intact. [14] 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 other lacking Nav1.7 in all DRG neurons as well as all sympathetic neurons, has revealed distinct sets of modality specific peripheral neurons. [15] 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 erythromelalgia (PE), an autosomal dominant, inherited disorder which is characterized by attacks or episodes of symmetrical burning 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 missense mutation in the SCN9A gene affected conserved residues in the pore-forming α subunit of the Nav1.7 channel. Multiple studies have found a dozen SCN9A mutations in multiple families as causing erythromelagia. [16] [17] All of the observed 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 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. [18] 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 (hyperalgesia). While the expression of PE Nav1.7 mutations produces hyperexcitability in DRG neurons, studies on cultured rat in 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 nociceptors and with sympathetic dysfunction that is most likely due to hypoexcitability of sympathetic ganglion neurons. [9] Recent studies have associated a defect in SCN9A with congenital insensitivity to pain. [19]

Paroxysmal extreme pain disorder

Paroxysmal extreme pain disorder (PEPD) is another rare, extreme pain disorder. [20] [21] Like primary erythromelalgia, PEPD is similarly the result of a gain-of-function mutation in the gene encoding the Nav1.7 channel. [20] [21] The decreased inactivation caused by the mutation is cause of prolonged action potentials and repetitive firing. Such altered firing will cause increased pain sensation and increased sympathetic nervous system activity, producing the phenotype observed in patients with PEPD. [22]

Congenital insensitivity to pain

Individuals with congenital insensitivity to pain have painless injuries beginning in infancy but otherwise normal sensory responses upon examination. Patients frequently have bruises and cuts, [23] 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 causes loss of Nav1.7 function has been detected in three consanguineous families from northern Pakistan. All mutations observed were nonsense mutation, with the majority of affected patients having a homozygous mutation in the SCN9A gene. This discovery linked loss of Nav1.7 function with the inability to experience pain. This is in contrast with the genetic basis of primary erythromelalgia in which the disorder results from gain-of-function mutations. [19]

Clinical analgesics

Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels. [24] [25] Nav1.7, as well as Nav1.3, Nav1.8, and Nav1.9, are the specific channels that have been implicated in pain signaling. [24] [26] Thus, the blockade of these specific channels is likely to underlie the analgesia of local anesthetics and anticonvulsants such as phenytoin. [24] In addition, inhibition of these channels is also likely responsible for the analgesic efficacy of certain tricyclic antidepressants, and of mexiletine. [27] [28]

Itch

Mutations of Nav1.7 have been linked to itching (pruritus), [29] [30] and genetic knockouts of Nav1.7 [31] and an antibody that inhibits Nav1.7 also appear to inhibit itching. [32] [33]

Future prospects

As the Nav1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia, [21] there has been immense interest in developing selective Nav1.7 channel blockers as potential novel analgesics. [34] 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 with fewer undesirable effects, relative to current pharmacotherapies. [34] [35] [36]

A number of selective Nav1.7 (and/or Nav1.8) blockers are in clinical development, including funapide (TV-45070, XEN402), PF-05089771, DSP-2230, NKTR-171, GDC-0276, and RG7893 (GDC-0287). [37] [38] [39] Ralfinamide (formerly NW-1029, FCE-26742A, PNU-0154339E) is a multimodal, non-selective Nav channel blocker which is under development for the treatment of pain. [40]

Surprisingly, many potent Nav1.7 blockers have been found to be clinically effective but only relatively weak analgesics. [41] Recently, it has been elucidated that congenital loss of Navv1.7 results in a dramatic increase in the levels of endogenous enkephalins, and it was found that blocking these opioids with the opioid antagonist naloxone allowed for pain sensitivity both in Navv1.7 null mice and in a woman with a defective Navv1.7 gene and associated congenital insensitivity to pain. [41] Development of the venom-derived peptide, JNJ63955 allowed for selective inhibition of Nav1.7 only while it was in the closed state, which produced results, in mice, much more similar to knock-out models. [42] [ unreliable medical source ] It is possible that channel blockade is maximal only when the channel is inhibited in its closed state. It appears that complete inactivation of Nav1.7-mediated sodium efflux is necessary to upregulate enkephalin expression enough to achieve complete analgesia. Prior to the development of JNJ63955, the most potent [Nav 1.7] antagonists had failed in regards to achieving the same degree of analgesia as congenital Nav1.7 inactivity. [41] The proposed mechanism also suggests that the analgesic effects of Nav1.7 blockers may be greatly potentiated by the co-administration of exogenous opioids or enkephalinase inhibitors. [41] Supporting this idea, a strong analgesic synergy between local anesthetics and topical opioids has already been observed in clinical research. [41]

An additional implication of the aforementioned findings is that congenital insensitivity to pain may be clinically treatable with opioid antagonists. [41]

In 2021, researchers described a novel approach, developing a CRISPR-dCas9 epigenome editing method for a potential treatment of chronic pain by repressing Nav1.7 gene expression which showed therapeutic potential in three mouse models of chronic pain. [43] [44]

Related Research Articles

Congenital insensitivity to pain (CIP), also known as congenital analgesia, is one or more extraordinarily rare conditions in which a person cannot feel physical pain. The conditions described here are separate from the HSAN group of disorders, which have more specific signs and cause. Because feeling physical pain is vital for survival, CIP is an extremely dangerous condition. It is common for people with the condition to die in childhood due to injuries or illnesses going unnoticed. Burn injuries are among the more common injuries.

<span class="mw-page-title-main">Erythromelalgia</span> Inflammation due to periodic blood vessel blockage

Erythromelalgia or Mitchell's disease is a rare vascular peripheral pain disorder in which blood vessels, usually in the lower extremities or hands, are episodically blocked, then become hyperemic and inflamed. There is severe burning pain and skin redness. The attacks are periodic and are commonly triggered by heat, pressure, mild activity, exertion, insomnia or stress. Erythromelalgia may occur either as a primary or secondary disorder. Secondary erythromelalgia can result from small fiber peripheral neuropathy of any cause, polycythemia vera, essential thrombocythemia, hypercholesterolemia, mushroom or mercury poisoning, and some autoimmune disorders. Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene SCN9A.

<span class="mw-page-title-main">Sodium channel</span> Transmembrane protein allowing sodium ions in and out

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.

Na<sub>v</sub>1.4 Protein found in humans

Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.

SCN5A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.

Small fiber peripheral neuropathy is a type of peripheral neuropathy that occurs from damage to the small unmyelinated and myelinated peripheral nerve fibers. These fibers, categorized as C fibers and small Aδ fibers, are present in skin, peripheral nerves, and organs. The role of these nerves is to innervate some skin sensations and help control autonomic function. It is estimated that 15–20 million people in the United States have some form of peripheral neuropathy.

T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel activation initiates contraction directly by allowing the cytosolic concentration to increase. Not only are T-type calcium channels known to be present within cardiac and smooth muscle, but they also are present in many neuronal cells within the central nervous system. Different experimental studies within the 1970s allowed for the distinction of T-type calcium channels from the already well-known L-type calcium channels. The new T-type channels were much different from the L-type calcium channels due to their ability to be activated by more negative membrane potentials, had small single channel conductance, and also were unresponsive to calcium antagonist drugs that were present. These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.

Na<sub>v</sub>1.9 Protein-coding gene in the species Homo sapiens

Sodium channel, voltage-gated, type XI, alpha subunit 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.

Paroxysmal extreme pain disorder originally named familial rectal pain syndrome, is a rare disorder whose most notable features are pain in the mandibular, ocular and rectal areas as well as flushing. PEPD often first manifests at the beginning of life, perhaps even in utero, with symptoms persisting throughout life. PEPD symptoms are reminiscent of primary erythromelalgia, as both result in flushing and episodic pain, though pain is typically present in the extremities for primary erythromelalgia. Both of these disorders have recently been shown to be allelic, both caused by mutations in the voltage-gated sodium channel NaV1.7 encoded by the gene SCN9A. A different mutation in the SCN9A ion channel causes congenital insensitivity to pain.

SCN1A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 1 subunit alpha (SCN1A), is a protein which in humans is encoded by the SCN1A gene.

SCN2A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 2 subunit alpha, is a protein that in humans is encoded by the SCN2A gene. Functional sodium channels contain an ion conductive alpha subunit and one or more regulatory beta subunits. Sodium channels which contain sodium channel protein type 2 subunit alpha are sometimes called Nav1.2 channels.

<span class="mw-page-title-main">SCN8A</span> Protein-coding gene in the species Homo sapiens

Sodium channel protein type 8 subunit alpha also known as Nav1.6 is a membrane protein encoded by the SCN8A gene. Nav1.6 is one sodium channel isoform and is the primary voltage-gated sodium channel at each node of Ranvier. The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system.

<span class="mw-page-title-main">SCN7A</span> Protein-coding gene in the species Homo sapiens

Nax is a protein that in humans is encoded by the SCN7A gene. It is a sodium channel alpha subunit expressed in the heart, the uterus and in glial cells of mice. It has low similarity to all nine other sodium channel alpha subunits (Nav1.1–1.9).

Na<sub>v</sub>1.8 Protein-coding gene in the species Homo sapiens

Nav1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene.

<span class="mw-page-title-main">Acid-sensing ion channel</span> Class of transport proteins

Acid-sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons permeable to Na+. ASIC1 also shows low Ca2+ permeability. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. These genes have splice variants that encode for several isoforms that are marked by a suffix. In mammals, acid-sensing ion channels (ASIC) are encoded by five genes that produce ASIC protein subunits: ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. Three of these protein subunits assemble to form the ASIC, which can combine into both homotrimeric and heterotrimeric channels typically found in both the central nervous system and peripheral nervous system. However, the most common ASICs are ASIC1a and ASIC1a/2a and ASIC3. ASIC2b is non-functional on its own but modulates channel activity when participating in heteromultimers and ASIC4 has no known function. On a broad scale, ASICs are potential drug targets due to their involvement in pathological states such as retinal damage, seizures, and ischemic brain injury.

<span class="mw-page-title-main">PF-05089771</span> Investigational analgesic drug

PF-05089771 is a selective, small-molecule Nav1.7 and Nav1.8 voltage-gated sodium channel blocker under development by Pfizer as a novel analgesic. As of June 2014, it has completed phase II clinical trials for wisdom tooth removal and primary erythromelalgia.

Voltage-gated sodium channels (VGSCs), also known as voltage-dependent sodium channels (VDSCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the sodium ion Na+. They are the main channels involved in action potential of excitable cells.

<span class="mw-page-title-main">Stephen Waxman</span> American neurologist and neuroscientist

Stephen George Waxman is an American neurologist and neuroscientist. He served as Chairman of the Department of Neurology at Yale School of Medicine, and Neurologist-in-Chief at Yale-New Haven Hospital from 1986 until 2009. As of 2023, he is the Bridget Flaherty Professor of Neurology, Neurobiology, and Pharmacology at Yale University. He founded the Yale University Neuroscience & Regeneration Research Center in 1988 and is its director. He previously held faculty positions at Harvard Medical School, MIT, and Stanford Medical School. He is also visiting professor at University College London. He is the editor-in-chief of The Neuroscientist.

Protoxin-II, also known as ProTx-II, PT-II or β/ω-TRTX-Tp2a, is a neurotoxin that inhibits certain voltage-gated calcium and voltage-gated sodium channels. This toxin is a 30-residue disulfide-rich peptide that has unusually high affinity and selectivity toward the human Nav1.7. channel.

Phlotoxin is a neurotoxin from the venom of the tarantula Phlogiellus that targets mostly voltage-sensitive sodium channels and mainly Nav1.7. The only non-sodium voltage-sensitive channel that is inhibited by Phlotoxin is Kv3.4. Nav1.4 and Nav1.6 seem to be Phlotoxin-1-sensitive to some extent as well.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000169432 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000075316 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Klugbauer N, Lacinova L, Flockerzi V, Hofmann F (March 1995). "Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells". The EMBO Journal. 14 (6): 1084–1090. doi:10.1002/j.1460-2075.1995.tb07091.x. PMC   398185 . PMID   7720699.
  6. ↑ Plummer NW, Meisler MH (April 1999). "Evolution and diversity of mammalian sodium channel genes". Genomics. 57 (2): 323–331. doi:10.1006/geno.1998.5735. PMID   10198179.
  7. ↑ Catterall WA, Goldin AL, Waxman SG (December 2005). "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels". Pharmacological Reviews. 57 (4): 397–409. doi:10.1124/pr.57.4.4. PMID   16382098. S2CID   7332624.
  8. ↑ Raymond CK, Castle J, Garrett-Engele P, Armour CD, Kan Z, Tsinoremas N, et al. (October 2004). "Expression of alternatively spliced sodium channel alpha-subunit genes. Unique splicing patterns are observed in dorsal root ganglia". The Journal of Biological Chemistry. 279 (44): 46234–46241. doi: 10.1074/jbc.M406387200 . PMID   15302875. S2CID   17753425.
  9. 1 2 Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG (May 2006). "A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons". Proceedings of the National Academy of Sciences of the United States of America. 103 (21): 8245–8250. Bibcode:2006PNAS..103.8245R. doi: 10.1073/pnas.0602813103 . PMC   1472458 . PMID   16702558.
  10. ↑ Catterall WA (2000). "Structure and regulation of voltage-gated Ca2+ channels". Annual Review of Cell and Developmental Biology. 16: 521–555. doi:10.1146/annurev.cellbio.16.1.521. PMID   11031246.
  11. 1 2 Cummins TR, Howe JR, Waxman SG (December 1998). "Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel". The Journal of Neuroscience. 18 (23): 9607–9619. doi:10.1523/JNEUROSCI.18-23-09607.1998. PMC   6793269 . PMID   9822722.
  12. ↑ Renganathan M, Cummins TR, Waxman SG (August 2001). "Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons". Journal of Neurophysiology. 86 (2): 629–640. doi:10.1152/jn.2001.86.2.629. PMID   11495938. S2CID   11579149.
  13. ↑ Shekdar K, Langer J, Venkatachalan S, Schmid L, Anobile J, Shah P, et al. (May 2021). "Cell engineering method using fluorogenic oligonucleotide signaling probes and flow cytometry". Biotechnology Letters. 43 (5): 949–958. doi:10.1007/s10529-021-03101-5. PMC   7937778 . PMID   33683511.
  14. ↑ Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA, Dickenson AH, et al. (August 2004). "Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain". Proceedings of the National Academy of Sciences of the United States of America. 101 (34): 12706–12711. Bibcode:2004PNAS..10112706N. doi: 10.1073/pnas.0404915101 . PMC   515119 . PMID   15314237.
  15. ↑ Minett MS, Nassar MA, Clark AK, Passmore G, Dickenson AH, Wang F, et al. (April 2012). "Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons". Nature Communications. 3 (4): 791. Bibcode:2012NatCo...3..791M. doi:10.1038/ncomms1795. PMC   3337979 . PMID   22531176.
  16. ↑ Dib-Hajj SD, Yang Y, Black JA, Waxman SG (January 2013). "The Na(V)1.7 sodium channel: from molecule to man". Nature Reviews. Neuroscience. 14 (1): 49–62. doi:10.1038/nrn3404. PMID   23232607. S2CID   5489010.
  17. ↑ Tang Z, Chen Z, Tang B, Jiang H (September 2015). "Primary erythromelalgia: a review". Orphanet Journal of Rare Diseases. 10: 127. doi: 10.1186/s13023-015-0347-1 . PMC   4589109 . PMID   26419464.
  18. ↑ Drenth JP, Michiels JJ (June 1994). "Erythromelalgia and erythermalgia: diagnostic differentiation". International Journal of Dermatology. 33 (6): 393–397. doi:10.1111/j.1365-4362.1994.tb04037.x. PMID   8056469. S2CID   3033396.
  19. 1 2 Golshani AE, Kamdar AA, Spence SC, Beckmann NM (August 2014). "Congenital indifference to pain: an illustrated case report and literature review". Journal of Radiology Case Reports. 8 (8): 16–23. doi:10.3941/jrcr.v8i8.2194. PMC   4242143 . PMID   25426241.
  20. 1 2 Allerton C, Fox D (2013). Pain Therapeutics: Current and Future Treatment Paradigms. Royal Society of Chemistry. pp. 146–148. ISBN   978-1-84973-645-9.
  21. 1 2 3 Kew JN, Davies CH (2010). Ion Channels: From Structure to Function. Oxford University Press. pp. 153–154. ISBN   978-0-19-929675-0.
  22. ↑ Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, et al. (December 2006). "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes". Neuron. 52 (5): 767–774. doi: 10.1016/j.neuron.2006.10.006 . PMID   17145499. S2CID   11715780.
  23. ↑ Peddareddygari LR, Oberoi K, Grewal RP (2014-09-18). "Congenital insensitivity to pain: a case report and review of the literature". Case Reports in Neurological Medicine. 2014: 141953. doi: 10.1155/2014/141953 . PMC   4182687 . PMID   25309764.
  24. 1 2 3 Mashour GA, Lydic R (7 September 2011). Neuroscientific Foundations of Anesthesiology. Oxford University Press. p. 154. ISBN   978-0-19-987546-7.
  25. ↑ Chahine M. Recent advances in voltage-gated sodium channels, their pharmacology and related diseases. Frontiers E-books. p. 90. ISBN   978-2-88919-128-4.
  26. ↑ Lamberth C, Dinges J (9 August 2012). Bioactive Heterocyclic Compound Classes: Pharmaceuticals. John Wiley & Sons. p. 127. ISBN   978-3-527-66448-1.
  27. ↑ Cairns BE (1 September 2009). Peripheral Receptor Targets for Analgesia: Novel Approaches to Pain Management. John Wiley & Sons. pp. 66–68. ISBN   978-0-470-52221-9.
  28. ↑ James WD, Berger T, Elston D (12 April 2015). "Cutaneous Vascular Diseases". Andrews' Diseases of the Skin: Clinical Dermatology. Elsevier Health Sciences. pp. 810–. ISBN   978-0-323-31969-0.
  29. ↑ Devigili G, Eleopra R, Pierro T, Lombardi R, Rinaldo S, Lettieri C, et al. (September 2014). "Paroxysmal itch caused by gain-of-function Nav1.7 mutation". Pain. 155 (9): 1702–1707. doi:10.1016/j.pain.2014.05.006. PMID   24820863. S2CID   24462006.
  30. ↑ "An SCN9A variant, known to cause pain, is now found to cause itch" (PDF). Pain.
  31. ↑ Gingras J, Smith S, Matson DJ, Johnson D, Nye K, Couture L, et al. (2014). "Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain". PLOS ONE. 9 (9): e105895. Bibcode:2014PLoSO...9j5895G. doi: 10.1371/journal.pone.0105895 . PMC   4154897 . PMID   25188265.
  32. ↑ Martz L. "Nav-i-gating antibodies for pain". SciBX.
  33. ↑ Yong S (May 22, 2014). "One Molecule To Block Both Pain And Itch".
  34. 1 2 Altman RB, Flockhart D, Goldstein DB (23 January 2012). Principles of Pharmacogenetics and Pharmacogenomics. Cambridge University Press. p. 224. ISBN   978-1-107-37747-9.
  35. ↑ Waxman SG (December 2006). "Neurobiology: a channel sets the gain on pain". Nature. 444 (7121): 831–832. Bibcode:2006Natur.444..831W. doi:10.1038/444831a. PMID   17167466. S2CID   4300362.
  36. ↑ Dib-Hajj SD, Cummins TR, Black JA, Waxman SG (November 2007). "From genes to pain: Na v 1.7 and human pain disorders". Trends in Neurosciences. 30 (11): 555–563. doi:10.1016/j.tins.2007.08.004. PMID   17950472. S2CID   15131517.
  37. ↑ Bagal SK, Chapman ML, Marron BE, Prime R, Storer RI, Swain NA (August 2014). "Recent progress in sodium channel modulators for pain". Bioorganic & Medicinal Chemistry Letters. 24 (16): 3690–3699. doi: 10.1016/j.bmcl.2014.06.038 . PMID   25060923.
  38. ↑ Martz L (2014). "Nav-i-gating antibodies for pain". Science-Business EXchange. 7 (23): 662. doi: 10.1038/scibx.2014.662 . ISSN   1945-3477.
  39. ↑ McMahon S, Koltzenburg M, Tracey I, Turk DC (2013). Wall & Melzack's Textbook of Pain (6 ed.). Elsevier Health Sciences. p. 508. ISBN   978-0-7020-4059-7. OCLC   1008841684.
  40. ↑ Simpson DM, McArthur JC, Dworkin RH (21 June 2012). Neuropathic Pain: Mechanisms, Diagnosis and Treatment. Oxford University Press. pp. 40–. ISBN   978-0-19-539470-2.
  41. 1 2 3 4 5 6 Minett MS, Pereira V, Sikandar S, Matsuyama A, Lolignier S, Kanellopoulos AH, et al. (December 2015). "Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7". Nature Communications. 6: 8967. Bibcode:2015NatCo...6.8967M. doi:10.1038/ncomms9967. PMC   4686868 . PMID   26634308.
  42. ↑ Flinspach M, Xu Q, Piekarz AD, Fellows R, Hagan R, Gibbs A, et al. (January 2017). "Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor". Scientific Reports. 7: 39662. Bibcode:2017NatSR...739662F. doi:10.1038/srep39662. PMC   5206724 . PMID   28045073.
  43. ↑ "Unique CRISPR gene therapy offers opioid-free chronic pain treatment". New Atlas. 11 March 2021. Retrieved 18 April 2021.
  44. ↑ Moreno AM, Alemán F, Catroli GF, Hunt M, Hu M, Dailamy A, et al. (March 2021). "Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice". Science Translational Medicine. 13 (584): eaay9056. doi:10.1126/scitranslmed.aay9056. PMC   8830379 . PMID   33692134. S2CID   232170826.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.