Biology:Nav1.7

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene.[1][2][3] It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at dorsal root ganglion (DRG) and trigeminal ganglion and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.[4][5]

Function

Structure of human voltage-gated sodium channel Nav1.7 in complex with auxiliary beta subunits, ProTx-II and tetrodotoxin (Y1755 down) from the RCSB PDB (6J8J).

Nav1.7 is a voltage-gated sodium channel and 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.[6] 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.[7] 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.[7] 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.[8]

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.[9]

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.[10] 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.[11] 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.[12][13] 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.[14] 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.[5] Recent studies have associated a defect in SCN9A with congenital insensitivity to pain.[15]

Paroxysmal extreme pain disorder

Paroxysmal extreme pain disorder (PEPD) is another rare, extreme pain disorder.[16][17] Like primary erythromelalgia, PEPD is similarly the result of a gain-of-function mutation in the gene encoding the Nav1.7 channel.[16][17] 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.[18]

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,[19] 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.[15]

Clinical analgesics

Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels.[20][21] Nav1.7, as well as Nav1.3, Nav1.8, and Nav1.9, are the specific channels that have been implicated in pain signaling.[20][22] Thus, the blockade of these specific channels is likely to underlie the analgesia of local anesthetics and anticonvulsants such as phenytoin.[20] In addition, inhibition of these channels is also likely responsible for the analgesic efficacy of certain tricyclic antidepressants, and of mexiletine.[23][24]

Itch

Mutations of Nav1.7 have been linked to itching (pruritus),[25][26] and genetic knockouts of Nav1.7[27] and an antibody that inhibits Nav1.7 also appear to inhibit itching.[28][29][30]

Future prospects

As the Nav1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia,[17] there has been immense interest in developing selective Nav1.7 channel blockers as potential novel analgesics.[31] 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.[31][32][33]

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).[34][35][36] 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.[37]

Surprisingly, many potent Nav1.7 blockers have been found to be clinically effective but only relatively weak analgesics.[38] 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.[38] 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.[39][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.[38] 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.[38] Supporting this idea, a strong analgesic synergy between local anesthetics and topical opioids has already been observed in clinical research.[38]

An additional implication of the aforementioned findings is that congenital insensitivity to pain may be clinically treatable with opioid antagonists.[38]

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.[40][41]

References

  1. ↑ "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): 1084–90. March 1995. doi:10.1002/j.1460-2075.1995.tb07091.x. PMID 7720699. 
  2. ↑ "Evolution and diversity of mammalian sodium channel genes". Genomics 57 (2): 323–31. April 1999. doi:10.1006/geno.1998.5735. PMID 10198179. 
  3. ↑ "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels". Pharmacological Reviews 57 (4): 397–409. December 2005. doi:10.1124/pr.57.4.4. PMID 16382098. 
  4. ↑ "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): 46234–41. October 2004. doi:10.1074/jbc.M406387200. PMID 15302875. 
  5. ↑ 5.0 5.1 "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): 8245–50. May 2006. doi:10.1073/pnas.0602813103. PMID 16702558. Bibcode: 2006PNAS..103.8245R. 
  6. ↑ "Structure and regulation of voltage-gated Ca2+ channels". Annual Review of Cell and Developmental Biology 16: 521–55. 2000. doi:10.1146/annurev.cellbio.16.1.521. PMID 11031246. 
  7. ↑ 7.0 7.1 "Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel". The Journal of Neuroscience 18 (23): 9607–19. December 1998. doi:10.1523/JNEUROSCI.18-23-09607.1998. PMID 9822722. 
  8. ↑ "Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons". Journal of Neurophysiology 86 (2): 629–40. August 2001. doi:10.1152/jn.2001.86.2.629. PMID 11495938. 
  9. ↑ "Cell engineering method using fluorogenic oligonucleotide signaling probes and flow cytometry". Biotechnology Letters 43 (5): 949–958. March 2021. doi:10.1007/s10529-021-03101-5. PMID 33683511. 
  10. ↑ "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): 12706–11. August 2004. doi:10.1073/pnas.0404915101. PMID 15314237. Bibcode: 2004PNAS..10112706N. 
  11. ↑ "Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons". Nature Communications 3 (4): 791–799. April 2012. doi:10.1038/ncomms1795. PMID 22531176. Bibcode: 2012NatCo...3..791M. 
  12. ↑ "The Na(V)1.7 sodium channel: from molecule to man". Nature Reviews. Neuroscience 14 (1): 49–62. January 2013. doi:10.1038/nrn3404. PMID 23232607. 
  13. ↑ "Primary erythromelalgia: a review". Orphanet Journal of Rare Diseases 10: 127. September 2015. doi:10.1186/s13023-015-0347-1. PMID 26419464. 
  14. ↑ "Erythromelalgia and erythermalgia: diagnostic differentiation". International Journal of Dermatology 33 (6): 393–7. June 1994. doi:10.1111/j.1365-4362.1994.tb04037.x. PMID 8056469. 
  15. ↑ 15.0 15.1 "Congenital indifference to pain: an illustrated case report and literature review". Journal of Radiology Case Reports 8 (8): 16–23. August 2014. doi:10.3941/jrcr.v8i8.2194. PMID 25426241. 
  16. ↑ 16.0 16.1 Pain Therapeutics: Current and Future Treatment Paradigms. Royal Society of Chemistry. 2013. pp. 146–148. ISBN 978-1-84973-645-9. https://books.google.com/books?id=zUINAgAAQBAJ&pg=PA146. 
  17. ↑ 17.0 17.1 17.2 Ion Channels: From Structure to Function. Oxford University Press. 2010. pp. 153–154. ISBN 978-0-19-929675-0. https://books.google.com/books?id=TAWdlOB-UUsC&pg=PA153. 
  18. ↑ "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes". Neuron 52 (5): 767–74. December 2006. doi:10.1016/j.neuron.2006.10.006. PMID 17145499. 
  19. ↑ "Congenital insensitivity to pain: a case report and review of the literature". Case Reports in Neurological Medicine 2014: 141953. 2014-09-18. doi:10.1155/2014/141953. PMID 25309764. 
  20. ↑ 20.0 20.1 20.2 Neuroscientific Foundations of Anesthesiology. Oxford University Press. 7 September 2011. p. 154. ISBN 978-0-19-987546-7. https://books.google.com/books?id=M0NpAgAAQBAJ&pg=PA154. 
  21. ↑ Mohamed Chahine. Recent advances in voltage-gated sodium channels, their pharmacology and related diseases. Frontiers E-books. p. 90. ISBN 978-2-88919-128-4. https://books.google.com/books?id=1IL_Q7UyYE8C&pg=PA90. 
  22. ↑ Bioactive Heterocyclic Compound Classes: Pharmaceuticals. John Wiley & Sons. 9 August 2012. p. 127. ISBN 978-3-527-66448-1. https://books.google.com/books?id=zk0cIhG4lIwC&pg=PA127. 
  23. ↑ 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. https://books.google.com/books?id=MTSvERxiCrIC&pg=PA66. 
  24. ↑ James, William D.; Berger, Timothy; Elston, Dirk (12 April 2015). Andrews' Diseases of the Skin: Clinical Dermatology. Elsevier Health Sciences. pp. 810–. ISBN 978-0-323-31969-0. https://books.google.com/books?id=Np6cCQAAQBAJ&pg=PA810. 
  25. ↑ "Paroxysmal itch caused by gain-of-function Nav1.7 mutation". Pain 155 (9): 1702–7. September 2014. doi:10.1016/j.pain.2014.05.006. PMID 24820863. 
  26. ↑ "An SCN9A variant, known to cause pain, is now found to cause itch". Pain. http://www.rosslab.neurobio.pitt.edu/wp-content/themes/rosslab-theme/files/preview_rosslab_pain_2014.pdf. 
  27. ↑ "Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain". PLOS ONE 9 (9): e105895. 2014. doi:10.1371/journal.pone.0105895. PMID 25188265. Bibcode: 2014PLoSO...9j5895G. 
  28. ↑ "A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief". Cell 157 (6): 1393–404. June 2014. doi:10.1016/j.cell.2014.03.064. PMID 24856969. 
  29. ↑ Martz, Lauren. "Nav-i-gating antibodies for pain". SciBX. http://www.nature.com/scibx/journal/v7/n23/full/scibx.2014.662.html. 
  30. ↑ Sheila Yong (May 22, 2014). "One Molecule To Block Both Pain And Itch". http://today.duke.edu/2014/05/painitch. 
  31. ↑ 31.0 31.1 Principles of Pharmacogenetics and Pharmacogenomics. Cambridge University Press. 23 January 2012. p. 224. ISBN 978-1-107-37747-9. https://books.google.com/books?id=7EAhAwAAQBAJ&pg=PA224. 
  32. ↑ "Neurobiology: a channel sets the gain on pain". Nature 444 (7121): 831–2. December 2006. doi:10.1038/444831a. PMID 17167466. Bibcode: 2006Natur.444..831W. 
  33. ↑ "From genes to pain: Na v 1.7 and human pain disorders". Trends in Neurosciences 30 (11): 555–63. November 2007. doi:10.1016/j.tins.2007.08.004. PMID 17950472. 
  34. ↑ "Recent progress in sodium channel modulators for pain". Bioorganic & Medicinal Chemistry Letters 24 (16): 3690–9. August 2014. doi:10.1016/j.bmcl.2014.06.038. PMID 25060923. 
  35. ↑ "Nav-i-gating antibodies for pain". Science-Business EXchange 7 (23): 662. 2014. doi:10.1038/scibx.2014.662. ISSN 1945-3477. 
  36. ↑ Wall & Melzack's Textbook of Pain: Expert Consult - Online. Elsevier Health Sciences. 1 March 2013. p. 508. ISBN 978-0-7020-5374-0. https://books.google.com/books?id=ok0_jIJ0w_wC&pg=PA508. 
  37. ↑ Neuropathic Pain: Mechanisms, Diagnosis and Treatment. Oxford University Press. 21 June 2012. pp. 40–. ISBN 978-0-19-539470-2. https://books.google.com/books?id=1fF7pRxFzZUC&pg=PA40. 
  38. ↑ 38.0 38.1 38.2 38.3 38.4 38.5 "Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7". Nature Communications 6: 8967. December 2015. doi:10.1038/ncomms9967. PMID 26634308. Bibcode: 2015NatCo...6.8967M. 
  39. ↑ "Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor". Scientific Reports 7: 39662. January 2017. doi:10.1038/srep39662. PMID 28045073. Bibcode: 2017NatSR...739662F. 
  40. ↑ "Unique CRISPR gene therapy offers opioid-free chronic pain treatment". New Atlas. 11 March 2021. https://newatlas.com/science/crispr-gene-therapy-opioid-free-chronic-pain-relief/. 
  41. ↑ Moreno, Ana M.; Alemán, Fernando; Catroli, Glaucilene F.; Hunt, Matthew; Hu, Michael; Dailamy, Amir; Pla, Andrew; Woller, Sarah A. et al. (10 March 2021). "Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice" (in en). Science Translational Medicine 13 (584): eaay9056. doi:10.1126/scitranslmed.aay9056. ISSN 1946-6234. PMID 33692134. 

Further reading

External links




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