Biology:TRPA1

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Short description: Protein and coding gene in humans


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

Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 (and in mice and rats by the Trpa1) gene.[1][2]

TRPA1 is an ion channel located on the plasma membrane of many human and animal cells. This ion channel is best known as a sensor for pain, cold and itch in humans and other mammals, as well as a sensor for environmental irritants giving rise to other protective responses (tears, airway resistance, and cough).[3][4]

Function

TRPA1 is a member of the transient receptor potential channel family.[2] TRPA1 contains 14 N-terminal ankyrin repeats and is believed to function as a mechanical and chemical stress sensor.[5] One of the specific functions of this protein studies involves a role in the detection, integration and initiation of pain signals in the peripheral nervous system.[6] It can be activated at sites of tissue injury or sites of inflammation directly by endogenous mediators or indirectly as a downstream target via signaling from a number of distinct G-protein coupled receptors (GPCRs), such as bradykinin.

Recent studies indicate that TRPA1 is activated by a number of reactive [3][4][7] (allyl isothiocyanate, cinnamaldehyde, farnesyl thiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases[8][9][10]) and non-reactive compounds (nicotine,[11] PF-4840154[12]) and is thus considered as a "chemosensor" in the body.[13] TRPA1 is co-expressed with TRPV1 on nociceptive primary afferent C-fibers in humans.[14] This sub-population of peripheral C-fibers is considered important sensors of nociception in humans and their activation will under normal conditions give rise to pain.[15] Indeed, TRPA1 is considered as an attractive pain target. TRPA1 knockout mice showed near complete attenuation of nocifensive behaviors to formalin, tear-gas and other reactive chemicals .[16][17] TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete Freund's adjuvant and formalin).

Although it is not firmly confirmed whether noxious cold sensation is mediated by TRPA1 in vivo, several recent studies clearly demonstrated cold activation of TRPA1 channels in vitro.[18][19]

In the heat-sensitive loreal pit organs of many snakes TRPA1 is responsible for the detection of infrared radiation.[20]

Snakes have this type of receptors in their pit organ to help them detect infrared radiation.[21] However, frogs such as Hyalinobatrachium fleischmanni can reflect infrared light with their skins and, if the environment also reflects infrared light, the frogs will not be discovered by the predators.[22]

Structure

In 2016, cryo-electron microscopy was employed to obtain a three-dimensional structure of TRPA1. This work revealed that the channel assembles as a homotetramer, and possesses several structural features that hint at its complex regulation by irritants, cytoplasmic second messengers (e.g., calcium), cellular co-factors (e.g., inorganic anions like polyphosphates), and lipids (e.g., PIP2). Most notably, the site of covalent modification and activation for electrophilic irritants was localized to a tertiary structural feature on the membrane-proximal intracellular face of the channel, which has been termed the 'allosteric nexus', and which is composed of a cysteine-rich linker domain and the eponymous TRP domain.[23] Breakthrough research combining cryo-electron microscopy and electrophysiology later elucidated the molecular mechanism of how the channel functions as a broad-spectrum irritant detector. With respect to electrophiles, which activate the channel by covalent modification of two cysteines in the allosteric nexus, it was shown that these reactive oxidative species act step-wise to modify two critical cysteine residues in the allosteric nexus. Upon covalent attachment, the allosteric nexus adopts a conformational change that is propagated to the channel's pore, dilating it to permit cation influx and subsequent cellular depolarization. With respect to activation by the second messenger calcium, the structure of the channel in complex with calcium localized the binding site for this ion and functional studies demonstrated that this site controls the various different effects of calcium on the channel – namely potentiation, desensitization, and receptor-operation.[24]

Clinical significance

In 2008, it was observed that caffeine suppresses activity of human TRPA1, but it was found that mouse TRPA1 channels expressed in sensory neurons cause an aversion to drinking caffeine-containing water, suggesting that the TRPA1 channels mediate the perception of caffeine.[25]

TRPA1 has also been implicated in airway irritation[26] by cigarette smoke,[27] cleaning supplies[10] and in the skin irritation experienced by some smokers trying to quit by using nicotine replacement therapies such as inhalers, sprays, or patches.[11] A missense mutation of TRPA1 was found to be the cause of a hereditary episodic pain syndrome. A family from Colombia suffers from debilitating upper-body pain starting in infancy that is usually triggered by fasting or fatigue (illness, cold temperature, and physical exertion being contributory factors). A gain-of-function mutation in the fourth transmembrane domain causes the channel to be overly sensitive to pharmacological activation.[28]

Metabolites of paracetamol (acetaminophen) have been demonstrated to bind to the TRPA1 receptors, which may desensitize the receptors in the way capsaicin does in the spinal cord of mice, causing an antinociceptive effect. This is suggested as the antinociceptive mechanism for paracetamol.[29]

Oxalate, a metabolite of an anti cancer drug oxaliplatin, has been demonstrated to inhibit prolyl hydroxylase, which endows cold-insensitive human TRPA1 with pseudo cold sensitivity (via reactive oxygen generation from mitochondria). This may cause a characteristic side-effect of oxaliplatin (cold-triggered acute peripheral neuropathy).[30]

Ligand binding

TRPA1 can be considered to be one of the most promiscuous TRP ion channels, as it seems to be activated by a large number of noxious chemicals found in many plants, food, cosmetics and pollutants.[31][32]

Activation of the TRPA1 ion channel by the olive oil phenolic compound oleocanthal appears to be responsible for the pungent or "peppery" sensation in the back of the throat caused by olive oil.[33][34]

Although several nonelectrophilic agents such as thymol and menthol have been reported as TRPA1 agonists, most of the known activators are electrophilic chemicals that have been shown to activate the TRPA1 receptor via the formation of a reversible covalent bond with cysteine residues present in the ion channel.[35][36] Another example of a nonelectrophilic agent is the anesthetic propofol, which is known to cause pain on injection into a vein, a side effect attributed to TRPV1 and TRPA1 activation.[37] For a broad range of electrophilic agents, chemical reactivity in combination with a lipophilicity enabling membrane permeation is crucial to TRPA1 agonistic effect. A dibenz[b,f][1,4]oxazepine derivative substituted by a carboxylic methylester at position 10 has been reported to be a potent TRPA1 agonist (EC50 = 0.13μM or pEC50 = 6.90).[38] The pyrimidine PF-4840154 is a potent, non-covalent activator of both the human (EC50 = 23 nM) and rat (EC50 = 97 nM) TRPA1 channels. This compound elicits nociception in a mouse model through TRPA1 activation. Furthermore, PF-4840154 is superior to allyl isothiocyanate, the pungent component of mustard oil, for screening purposes.[12] Other TRPA1 channel activators include JT-010 and ASP-7663, while channel blockers include A-967079, HC-030031 and AM-0902.

The eicosanoids formed in the ALOX12 (i.e. arachidonate-12-lipoxygnease) pathway of arachidonic acid metabolism, 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (i.e. 12S-HpETE; see 12-Hydroxyeicosatetraenoic acid) and the hepoxilins (Hx), HxA3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid) (see Hepoxilin) directly activate TRPA1 and thereby contribute to the hyperalgesia and tactile allodynia responses of mice to skin inflammation. In this animal model of pain perception, the hepoxilins are released in the spinal cord directly activate TRPA (and also TRPV1) receptors to augment the perception of pain.[39][40][41][42] 12S-HpETE, which is the direct precursor to HxA3 and HxB3 in the ALOX12 pathway, may act only after being converted to these hepoxilins.[41] The epoxide, 5,6-epoxy-8Z,11Z,14Z-eicosatrienoic acid (5,6-EET) made by the metabolism of arachidonic acid by any one of several cytochrome P450 enzymes (see Epoxyeicosatrienoic acid) likewise directly activates TRPA1 to amplify pain perception.[41]

Studies with mice, guinea pigs, and human tissues indicate that another arachidonic acid metabolite, Prostaglandin E2, operates through its prostaglandin EP3 G protein coupled receptor to trigger cough responses. Its mechanism of action does not appear to involve direct binding to TRPA1 but rather the indirect activation and/or sensitization of TRPA1 as well as TRPV1 receptors. Genetic polymorphism in the EP3 receptor (rs11209716[43]), has been associated with ACE inhibitor-induce cough in humans.[44][45]

More recently, a peptide toxin termed the wasabi receptor toxin from the Australian black rock scorpion (Urodacus manicatus) was discovered; it was shown to bind TRPA1 non-covalently in the same region as electrophiles and act as a gating modifier toxin for the receptor, stabilizing the channel in an open conformation.[46]

TRPA1 inhibition

A number of small molecule inhibitors (antagonists) have been discovered which have been shown to block the function of TRPA1. [47] At the cellular level, assays that measure agonist-activated inhibition of TRPA1-mediated calcium fluxes and electrophysiological assays have been used to characterize the potency, species specificity and mechanism of inhibition. While the earliest inhibitors, such as HC-030031, were lower potency (micromolar inhibition) and had limited TRPA1 specificity, the more recent discovery of highly potent inhibitors with low nanomolar inhibition constants, such as A-967079 and ALGX-2542 as well as high selectivity among other members the TRP superfamily and lack of interaction with other targets have provided valuable tool compounds and candidates for future drug development.[47][48][49]

Resolvin D1 (RvD1) and RvD2 (see resolvins) and maresin 1 are metabolites of the omega 3 fatty acid, docosahexaenoic acid. They are members of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, in humans. These SPMs also damp pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effect involves the inhibition of TRPA1, probably (in at least certain cases) by an indirect effect wherein they activate another receptor located on neurons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which SPMs may operate to down-regulate TRPs and thereby pain perception.[50][51][52][53][54]

Ligand examples

Agonists

Gating Modifiers

Antagonists

  • HC-030031
  • GRC17536
  • A-967079
  • ALGX-2513
  • ALGX-2541
  • ALGX-2563
  • ALGX-2561
  • ALGX-2542 [47]

References

  1. ↑ "An ankyrin-like protein with transmembrane domains is specifically lost after oncogenic transformation of human fibroblasts". The Journal of Biological Chemistry 274 (11): 7325–33. March 1999. doi:10.1074/jbc.274.11.7325. PMID 10066796. 
  2. ↑ 2.0 2.1 "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews 57 (4): 427–50. December 2005. doi:10.1124/pr.57.4.6. PMID 16382100. 
  3. ↑ 3.0 3.1 "Human surrogate models of histaminergic and non-histaminergic itch". Acta Dermato-Venereologica 95 (7): 771–7. September 2015. doi:10.2340/00015555-2146. PMID 26015312. 
  4. ↑ 4.0 4.1 "A human surrogate model of itch utilizing the TRPA1 agonist trans-cinnamaldehyde". Acta Dermato-Venereologica 95 (7): 798–803. September 2015. doi:10.2340/00015555-2103. PMID 25792226. http://vbn.aau.dk/files/219083560/4403_9.pdf. 
  5. ↑ "TRPA1". Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology. 179. 2007. pp. 347–62. doi:10.1007/978-3-540-34891-7_21. ISBN 978-3-540-34889-4. 
  6. ↑ "Entrez Gene: TRPA1 transient receptor potential cation channel, subfamily A, member 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8989. 
  7. ↑ "Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti-inflammatory agents". Journal of Medicinal Chemistry 53 (14): 5085–107. July 2010. doi:10.1021/jm100062h. PMID 20356305. 
  8. ↑ "Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor". Toxicology and Applied Pharmacology 231 (2): 150–6. September 2008. doi:10.1016/j.taap.2008.04.005. PMID 18501939. 
  9. ↑ "Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases". FASEB Journal 23 (4): 1102–14. April 2009. doi:10.1096/fj.08-117812. PMID 19036859. 
  10. ↑ 10.0 10.1 "TRPA1 is a major oxidant sensor in murine airway sensory neurons". The Journal of Clinical Investigation 118 (5): 1899–910. May 2008. doi:10.1172/JCI34192. PMID 18398506. 
  11. ↑ 11.0 11.1 "Nicotine activates the chemosensory cation channel TRPA1". Nature Neuroscience 12 (10): 1293–9. October 2009. doi:10.1038/nn.2379. PMID 19749751. https://lirias.kuleuven.be/handle/123456789/247611. 
  12. ↑ 12.0 12.1 "Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel". Bioorganic & Medicinal Chemistry Letters 21 (16): 4857–9. August 2011. doi:10.1016/j.bmcl.2011.06.035. PMID 21741838. 
  13. ↑ "TRPA1: the central molecule for chemical sensing in pain pathway?". The Journal of Neuroscience 28 (5): 1019–21. January 2008. doi:10.1523/JNEUROSCI.5237-07.2008. PMID 18234879. 
  14. ↑ "Psychophysical and vasomotor evidence for interdependency of TRPA1 and TRPV1-evoked nociceptive responses in human skin: an experimental study". Pain 159 (10): 1989–2001. October 2018. doi:10.1097/j.pain.0000000000001298. PMID 29847470. http://vbn.aau.dk/da/publications/psychophysical-and-vasomotor-evidence-for-interdependency-of-trpa1-and-trpv1evoked-nociceptive-responses-in-human-skin(2a5a00a0-3e6f-4014-9c4b-c1db7c9efebc).html. 
  15. ↑ "Dose-response study of topical allyl isothiocyanate (mustard oil) as a human surrogate model of pain, hyperalgesia, and neurogenic inflammation". Pain 158 (9): 1723–1732. September 2017. doi:10.1097/j.pain.0000000000000979. PMID 28614189. http://vbn.aau.dk/ws/files/259882497/00006396_900000000_99224.pdf. 
  16. ↑ "TRPA1 mediates formalin-induced pain". Proceedings of the National Academy of Sciences of the United States of America 104 (33): 13525–30. August 2007. doi:10.1073/pnas.0705924104. PMID 17686976. Bibcode: 2007PNAS..10413525M. 
  17. ↑ "Increasingly irritable and close to tears: TRPA1 in inflammatory pain". Cell 124 (6): 1123–5. March 2006. doi:10.1016/j.cell.2006.03.006. PMID 16564004. 
  18. ↑ "Cold sensitivity of recombinant TRPA1 channels". Brain Research 1160: 39–46. July 2007. doi:10.1016/j.brainres.2007.05.047. PMID 17588549. 
  19. ↑ "Species-specific pharmacology of Trichloro(sulfanyl)ethyl benzamides as transient receptor potential ankyrin 1 (TRPA1) antagonists". Molecular Pain 3: 1744-8069-3-39. December 2007. doi:10.1186/1744-8069-3-39. PMID 18086308. 
  20. ↑ "Molecular basis of infrared detection by snakes". Nature 464 (7291): 1006–11. April 2010. doi:10.1038/nature08943. PMID 20228791. Bibcode: 2010Natur.464.1006G. 
  21. ↑ Geng, Jie; Liang, Dan; Jiang, Ke; Zhang, Peng (2011-12-07). "Molecular Evolution of the Infrared Sensory Gene TRPA1 in Snakes and Implications for Functional Studies" (in en). PLOS ONE 6 (12): e28644. doi:10.1371/journal.pone.0028644. ISSN 1932-6203. PMID 22163322. Bibcode: 2011PLoSO...628644G. 
  22. ↑ Schwalm, Patricia A.; Starrett, Priscilla H.; McDiarmid, Roy W. (1977-06-10). "Infrared Reflectance in Leaf-Sitting Neotropical Frogs" (in en). Science 196 (4295): 1225–1226. doi:10.1126/science.860137. ISSN 0036-8075. PMID 860137. Bibcode: 1977Sci...196.1225S. https://www.science.org/doi/10.1126/science.860137. 
  23. ↑ "Structure of the TRPA1 ion channel suggests regulatory mechanisms". Nature 520 (7548): 511–7. April 2015. doi:10.1038/nature14367. PMID 25855297. Bibcode: 2015Natur.520..511P. 
  24. ↑ "Irritant-evoked activation and calcium modulation of the TRPA1 receptor". Nature 585 (7823): 141–145. July 2020. doi:10.1038/s41586-020-2480-9. PMID 32641835. Bibcode: 2020Natur.585..141Z. 
  25. ↑ "Caffeine activates mouse TRPA1 channels but suppresses human TRPA1 channels". Proceedings of the National Academy of Sciences of the United States of America 105 (45): 17373–8. November 2008. doi:10.1073/pnas.0809769105. PMID 18988737. Bibcode: 2008PNAS..10517373N. 
  26. ↑ "Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control". Physiology 23 (6): 360–70. December 2008. doi:10.1152/physiol.00026.2008. PMID 19074743. 
  27. ↑ "Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents". The Journal of Clinical Investigation 118 (7): 2574–82. July 2008. doi:10.1172/JCI34886. PMID 18568077. 
  28. ↑ "A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome". Neuron 66 (5): 671–80. June 2010. doi:10.1016/j.neuron.2010.04.030. PMID 20547126. 
  29. ↑ "TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ(9)-tetrahydrocannabiorcol". Nature Communications 2 (2): 551. November 2011. doi:10.1038/ncomms1559. PMID 22109525. Bibcode: 2011NatCo...2..551A. 
  30. ↑ "Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS". Nature Communications 7: 12840. September 2016. doi:10.1038/ncomms12840. PMID 27628562. Bibcode: 2016NatCo...712840M. 
  31. ↑ Boonen, Brett; Startek, Justyna B.; Talavera, Karel (2016-01-01). Taste and Smell. Topics in Medicinal Chemistry. 23. Springer Berlin Heidelberg. pp. 1–41. doi:10.1007/7355_2015_98. ISBN 978-3-319-48925-4. 
  32. ↑ "Sensory detection and responses to toxic gases: mechanisms, health effects, and countermeasures". Proceedings of the American Thoracic Society 7 (4): 269–77. July 2010. doi:10.1513/pats.201001-004SM. PMID 20601631. 
  33. ↑ "Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal". The Journal of Neuroscience 31 (3): 999–1009. January 2011. doi:10.1523/JNEUROSCI.1374-10.2011. PMID 21248124. 
  34. ↑ "Sensory characterization of the irritant properties of oleocanthal, a natural anti-inflammatory agent in extra virgin olive oils". Chemical Senses 34 (4): 333–9. May 2009. doi:10.1093/chemse/bjp006. PMID 19273462. 
  35. ↑ "TRP channel activation by reversible covalent modification". Proceedings of the National Academy of Sciences of the United States of America 103 (51): 19564–8. December 2006. doi:10.1073/pnas.0609598103. PMID 17164327. Bibcode: 2006PNAS..10319564H. 
  36. ↑ 36.0 36.1 "Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines". Nature 445 (7127): 541–5. February 2007. doi:10.1038/nature05544. PMID 17237762. Bibcode: 2007Natur.445..541M. 
  37. ↑ Fischer, Michael J. M.; Leffler, Andreas; Niedermirtl, Florian; Kistner, Katrin; Eberhardt, Mirjam; Reeh, Peter W.; Nau, Carla (2010-11-05). "The general anesthetic propofol excites nociceptors by activating TRPV1 and TRPA1 rather than GABAA receptors". The Journal of Biological Chemistry 285 (45): 34781–34792. doi:10.1074/jbc.M110.143958. ISSN 1083-351X. PMID 20826794. 
  38. ↑ "Analogues of morphanthridine and the tear gas dibenz[b,f][1,4]oxazepine (CR) as extremely potent activators of the human transient receptor potential ankyrin 1 (TRPA1) channel". Journal of Medicinal Chemistry 53 (19): 7011–20. October 2010. doi:10.1021/jm100477n. PMID 20806939. 
  39. ↑ "Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors". Proceedings of the National Academy of Sciences of the United States of America 109 (17): 6721–6. April 2012. doi:10.1073/pnas.1110460109. PMID 22493235. Bibcode: 2012PNAS..109.6721G. 
  40. ↑ "Systematic analysis of rat 12/15-lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia". FASEB Journal 27 (5): 1939–49. May 2013. doi:10.1096/fj.12-217414. PMID 23382512. 
  41. ↑ 41.0 41.1 41.2 "TRPA1: a transducer and amplifier of pain and inflammation". Basic & Clinical Pharmacology & Toxicology 114 (1): 50–5. January 2014. doi:10.1111/bcpt.12138. PMID 24102997. 
  42. ↑ "Pathophysiology of the hepoxilins". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1851 (4): 383–96. April 2015. doi:10.1016/j.bbalip.2014.09.007. PMID 25240838. 
  43. ↑ "Reference SNP (refSNP) Cluster Report: Rs11209716". https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=11209716&pt=1-qmUGHsLMC5BR3la78zzEFD7-YFKRZ0LTSVR2ExVBUrQRWkr2. 
  44. ↑ "G-protein coupled receptors regulating cough". Current Opinion in Pharmacology 11 (3): 248–53. June 2011. doi:10.1016/j.coph.2011.06.005. PMID 21727026. 
  45. ↑ "Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough". Pharmacogenetics and Genomics 21 (1): 10–7. January 2011. doi:10.1097/FPC.0b013e328341041c. PMID 21052031. 
  46. ↑ 46.0 46.1 "A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain". Cell 178 (6): 1362–1374.e16. September 2019. doi:10.1016/j.cell.2019.07.014. PMID 31447178. 
  47. ↑ 47.0 47.1 47.2 "Novel TRPA1 Antagonists are Multimodal Blockers of Human TRPA1 Channels: Drug Candidates for Treatment of Familial Episodic Pain Syndrome (FEPS)" (in en). The FASEB Journal 34 (S1): 1. 2020. doi:10.1096/fasebj.2020.34.s1.02398. 
  48. ↑ "A Novel Class of Potent, Allosteric TRPA1 Antagonists Reverse Hyperalgesia in Multiple Rat Models of Neuropathic Pain". Experimental Biology 2016 Meeting. 30. 2016. pp. 927.3. doi:10.1096/fasebj.30.1_supplement.927.3. 
  49. ↑ "The discovery of a potent series of carboxamide TRPA1 antagonists". MedChemComm 7 (11): 2145–2158. 2016-11-08. doi:10.1039/C6MD00387G. 
  50. ↑ "Roles of resolvins in the resolution of acute inflammation". Cell Biology International 39 (1): 3–22. January 2015. doi:10.1002/cbin.10345. PMID 25052386. 
  51. ↑ "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology 7 (2): a016311. October 2014. doi:10.1101/cshperspect.a016311. PMID 25359497. 
  52. ↑ "Biological Roles of Resolvins and Related Substances in the Resolution of Pain". BioMed Research International 2015: 830930. 2015. doi:10.1155/2015/830930. PMID 26339646. 
  53. ↑ "Emerging roles of resolvins in the resolution of inflammation and pain". Trends in Neurosciences 34 (11): 599–609. November 2011. doi:10.1016/j.tins.2011.08.005. PMID 21963090. 
  54. ↑ "The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution". Seminars in Immunology 27 (3): 200–15. May 2015. doi:10.1016/j.smim.2015.03.004. PMID 25857211. 

External links



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