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==Your Heading Here (maybe something like 'Structure')==
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== The Transient Receptor Potential cation channel subfamily V member 1 TRPV1 ==
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<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
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<StructureSection load='5IS0' size='340' side='right' caption='Structure of TRPV1 in complex with capsazepine, determined in lipid nano disc, capsazepine is a synthetic antagonist of capsaicin' scene=''.>
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This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.
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You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
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== Function ==
 
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== Disease ==
 
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== Relevance ==
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== Introduction ==
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== Structural highlights ==
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[https://en.wikipedia.org/wiki/TRPV1 TRPV1] (Vanilloid Transient Receptor Potential Type 1) is a non-selective ion channel which, in response to a stimulus, induces an incoming current of cations, primarily calcium and sodium, that causes depolarization of the cell. It is part of the [https://en.wikipedia.org/wiki/Transient_receptor_potential_channel TRP] (Transient Receptor Potential) superfamily and is the first in a subfamily of vanilloid-sensitive TRP channels: TRPVs.TRPV1 is expressed in [https://en.wikipedia.org/wiki/Group_A_nerve_fiber Group A nerve fiber] and [https://en.wikipedia.org/wiki/Group_C_nerve_fiber Group C nerve fiber] by sensory neurons of the dorsal and trigeminal spinal ganglia. (Gastrointestinal tract’s neurons express this receptor widely which may be involved in Crohn's disease. TRPV1 is also located on the heart peri vascularisation. It has a vasodilatation effect and protects this organ via the substance it releases.) TRPV1 is implicated in [https://en.wikipedia.org/wiki/Nociception nociception], its activation by heat or by chemical substances leads to a painful sensation.<ref name="TRPV1">Wikipedia contributors. (2020, december 21). TRPV1. Wikipedia. https://en.wikipedia.org/wiki/TRPV1 (Consulted the: dec. 28, 2020). [Online].</ref> Functional and structural studies of TRPV1 have contributed to a clearer understanding of transmission of nociceptive stimuli mechanisms especially with low diameter fibers. TRPV1 has a major role in inflammatory and pain sensitivity and overactivation of TRPV1 increases the sensitivity to pain as well as extended pain induces overexpression of TRPV1 in nerve fibers. However, sub-expression of this receptor induces chronic pain. Which can appear with abnormal neuromodulators transport due to axonal damage.
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TRPV1 can be indirectly activated by NGF (nerve growth factor) and specific molecules of the inflammatory system such as bradykinin, serotonin, histamin, prostaglandin or ATP. They increase the channel opening, by blocking the PIP2 inhibition or by decreasing the heat activation threshold.
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<ref name="TRPV1 dans les neuropathies douloureuses"> A. Danigo, L. Magy et C. Demiot , Med Sci (Paris) Volume 29, Number 6-7, Juin–Juillet 2013, p. 597-606. TRPV1 dans les neuropathies douloureuses, https://www.medecinesciences.org/en/articles/medsci/full_html/2013/08/medsci2013296-7p597/medsci2013296-7p597.html, (Consulted the : dec. 23, 2021). [Online].</ref>
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== Structure of TRPV1 ==
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[[Image:TRPV1 Struct.jpg| thumb| Schematic figure of the TRPV1 receptor]]
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The TRPV1 receptor is a transmembrane protein receptor. It is made up of '''839 amino acids'''. It’s molecular weight is '''94 938Da'''.<ref name="Structure of the TRPV1 ion channel determined by electron cryo-microscopy">Liao, M., Cao, E., Julius, D., & Cheng, Y. (2013b). Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature, 504(7478), 107‑112. https://doi.org/10.1038/nature12822(consulté le déc. 28, 2020)</ref> TRPV1 exists in two states : the open state and the closed state.<ref> T. Rosenbaum et S. A. Simon, « TRPV1 Receptors and Signal Transduction », in TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades, W. B. Liedtke et S. Heller, Éd. Boca Raton (FL): CRC Press/Taylor & Francis, 2007</ref>
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TRPV1 are '''tetrameric''' channel type receptors. The four subunits form a symmetry plane around a pore allowing the passage of ions.
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Each TRPV1 subunits is made of one '''N-terminal tail''', one '''transmembrane region''', a '''C-terminal tail''' preceded by a '''TRP domain'''. The N-terminal and C-terminal region are intracellular. N and C terminal region are responsible of 70% of the total mass of TRPV1.<ref name="Structure of the TRPV1 ion channel determined by electron cryo-microscopy"/>
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The<scene name='86/868185/Aterm/1'> N-terminal</scene> region has 6 repeats of [https://en.wikipedia.org/wiki/Ankyrin <scene name='86/868185/Ankyrin_residues_of_n-term/1'>ankyrin</scene>].<ref name="Structure of the TRPV1 ion channel determined by electron cryo-microscopy"/><ref name="Integrating TRPV1 Receptor Function with Capsaicin Psychophysics">G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016</ref>
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The transmembrane region is composed of '''six transmembrane a helices''' (<scene name='86/868185/S1/1'>S1</scene>,<scene name='86/868185/S2/1'>S2</scene>,<scene name='86/868185/S3/1'>S3</scene>,<scene name='86/868185/S4/1'>S4</scene>,<scene name='86/868185/S5/1'>S5</scene>,<scene name='86/868185/S6/1'>S6</scene>). S1,S2 and S3 helices contain aromatic side chain (<scene name='86/868185/Y511_s512_t550/2'>Y511,S512,T550</scene>).<ref name="Structure of the TRPV1 ion channel determined by electron cryo-microscopy"/> A small hydrophobic domain beetween S5 and S6 with a <scene name='86/868185/Re_entrant_loop/1'>re-entrant loop</scene> constitutes the pore allowing the passage of ions through the TRPV1 receptor.<ref name="TRPV1"/><ref name="Structure of the TRPV1 ion channel determined by electron cryo-microscopy"/>
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'''Threonin''' residue (<scene name='86/868185/T550/1'>T550</scene>) and '''Tyrosin''' residue (<scene name='86/868185/Y511/2'>Y511</scene>) located on the fifth and the third transmembrane helices are very conserved. Threonin 550 and Tyrosin 511 are implicated in TRPV1 activation by [https://en.wikipedia.org/wiki/Vanilloids vanilloids] and in pain sensation.<ref>R. Kumar, A. Hazan, A. Basu, N. Zalcman, H. Matzner, et A. Priel, « Tyrosine Residue in the TRPV1 Vanilloid Binding Pocket Regulates Deactivation Kinetics », J. Biol. Chem., vol. 291, no 26, p. 13855‑13863, juin 2016, doi: 10.1074/jbc.M116.726372.</ref>
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The S6 domain links the receptor to the <scene name='86/868185/C_term/1'>C-terminal</scene> domain of TRPV1. The C-terminal is made of 150 amino acids and it contains '''<scene name='86/868185/Trp/1'>TRP domain</scene>'''.<ref name="Integrating TRPV1 Receptor Function with Capsaicin Psychophysics"/>.The TRP domain is made of 23-25 aminoacids with a alpha helical structure, it is found in many TRP family members.<ref name="Structure of the TRPV1 ion channel determined by electron cryo-microscopy"/> TRP domain is necessary for the formation of tetrameric TRPV1.
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Many amino-acids of the C-terminal domain are the target of post-translationnal modifications by [https://en.wikipedia.org/wiki/Kinase kinases] and [https://en.wikipedia.org/wiki/Phosphatase phosphatases].<ref>X. Yao, H.-Y. Kwan, et Y. Huang, « Regulation of TRP Channels by Phosphorylation », Neurosignals, vol. 14, no 6, p. 273‑280, 2005, doi: 10.1159/000093042</ref>
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== Relation structure-function ==
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TRPV1 is a '''homotetramer''' in which each subunit has several phosphorylation sites for '''PKA''' (protein kinase A), '''PKC''' (protein kinase C) and '''CaMkII''' (Ca2 + / calmodulin-dependent kinase II), as well as numerous glycosylation sites. These domains play a crucial role in the regulation of TRPV1 activity.
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The state of the channel is modulated by two types of molecules: agents that promote its opening of the channel, called [https://en.wikipedia.org/wiki/Agonist agonists], and agents that induce its closure or prevent its opening, called [https://en.wikipedia.org/wiki/Antagonist antagonists].
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=== Agonists ===
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====Capsaicin====
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[[Image:128px-Capsaicin Formulae.png | thumb|Chemical structure of capsaicin]]
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[https://en.wikipedia.org/wiki/Capsaicin Capsaicin] is an active compound in chili.
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TRPV1 receptor has a '''capsaicin-binding pocket''' formed by S3,S4 and <scene name='86/868185/S4s5_linker/1'>S4-S5 linker</scene>. The capsaicin-binding pocket is surrounded by the residues <scene name='86/868185/Y511_s512_t550/2'>Y511,S512,T550</scene>.<ref>F. Yang et J. Zheng, « Understand spiciness: mechanism of TRPV1 channel activation by capsaicin », Protein Cell, vol. 8, no 3, p. 169‑177, mars 2017, doi: 10.1007/s13238-016-0353-7.</ref>
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Bound capsaicin is oriented in a « tail-up, head down » configuration. In this configuration,capsaicin is anchored into the receptor.<ref>F. Yang et al., « Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel », Nat. Chem. Biol., vol. 11, no 7, Art. no 7, juill. 2015, doi: 10.1038/nchembio.1835.</ref>
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The capsaicin cycle binds via hydrogen bounds to amino acids on the S3 helix (<scene name='86/868185/Y511/1'>Y511</scene>), on the <scene name='86/868185/S4s5_linker/2'>S4-S5 linker</scene> and on the S6 helix (<scene name='86/868185/Tyr671/1'>T671</scene>). The amid group of capsaicin binds the <scene name='86/868185/S4/2'>S4</scene> helix.<ref name="Integrating TRPV1 Receptor Function with Capsaicin Psychophysics">
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Capsaicin maintains TRPV1 in an open state by «pull and contact» interactions. A conformational change wave spread over the whole pore.<ref>F. Yang et al., « The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel », Nat. Commun., vol. 9, no 1, Art. no 1, juill. 2018, doi: 10.1038/s41467-018-05339-6.</ref>.
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Capsaicin maintains TRPV1 in an open state. A conformational change wave spread over the whole pore.<ref>F. Yang et al., « The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel », Nat. Commun., vol. 9, no 1, Art. no 1, juill. 2018, doi: 10.1038/s41467-018-05339-6.</ref>. This leads to the massive enter of Ca2+ and Na+ and the depolarization of the nerve fiber. Depolarization triggers the generation of an [https://en.wikipedia.org/wiki/Action_potential action potential] causing a painful sensation.<ref name="TRPV1"/> Ca2+ has a negative retrospection effect on TRPV1 and induces a desensitization of this receptor facing capsaicin.
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<ref name="TRPV1 dans les neuropathies douloureuses"> A. Danigo, L. Magy et C. Demiot , Med Sci (Paris) Volume 29, Number 6-7, Juin–Juillet 2013, p. 597-606. TRPV1 dans les neuropathies douloureuses, https://www.medecinesciences.org/en/articles/medsci/full_html/2013/08/medsci2013296-7p597/medsci2013296-7p597.html, (Consulted the : dec. 23, 2021). [Online].</ref>
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====Resiniferatoxin (RTX)====
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[[Image:Resiniferatoxin.png | thumb | Chemical structure of resiniferatoxine]]
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[https://en.wikipedia.org/wiki/Resiniferatoxin Resiniferatoxin] is a '''natural analogue of capsaicin'''. It is the most potent TRPV1 agonist known, with a binding affinity for TRPV1 ~500x higher than that of capsaicin.
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The pocket size characteristics of the TRPV1-RTX allow the installation of RTX : The '''sub-pocket''' near <scene name='86/868185/Y511/2'>Y511</scene> is shallow in the TRPV1-RTX because <scene name='86/868185/Y511/2'>Y511</scene> and <scene name='86/868185/E570/2'>E570</scene> are close and <scene name='86/868185/I569/1'>I569</scene> is oriented towards the vanilloid pocket.<ref name="Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin">K. Elokely et al., « Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin », Proc. Natl. Acad. Sci., vol. 113, no 2, p. E137‑E145, janv. 2016, doi:10.1073/pnas.1517288113.</ref>
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The sub-pocket near <scene name='86/868185/L669/1'>L669</scene>, <scene name='86/868185/V583/1'>V583</scene> and <scene name='86/868185/F587/1'>F587</scene> accommodates the [https://en.wikipedia.org/wiki/Diterpene diterpene] group of the RTX.<ref name="Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin"/>
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The aromatic part of resiniferatoxin is located deeper in the sub-pocket near <scene name='86/868185/Y511/2'>Y511</scene> and is oriented almost parallel to the aromatic side chain of <scene name='86/868185/Y511/2'>Y511</scene>, so it establishes a strong interaction π-π. The aromatic hydroxyl and methoxy groups of the RTX form strong hydrogen bonds with <scene name='86/868185/E570/2'>E570</scene>, <scene name='86/868185/R557/1'>R557</scene> and <scene name='86/868185/S512/1'>S512</scene>. The ester group is linked to <scene name='86/868185/Y511/2'>Y511</scene> and <scene name='86/868185/T550/2'>T550</scene> by hydrogen bonds.
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=== Regulation ===
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====Sensitization====
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'''Phosphorylation''' of the TRPV1 receptor leads to its sensitization
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(the process regulates TRPV1 its functionality). Phosphorylations are either caused by '''PKC''' ([https://en.wikipedia.org/wiki/Inositol_trisphosphate IP3 signalling]), by '''PKA''' ([https://fr.wikipedia.org/wiki/Adénylate_cyclase AMPc signalling]), or by '''CamKII''' activation by inflammatory mediators. <ref name="Integrating TRPV1 Receptor Function with Capsaicin Psychophysics"> <ref>K. W. Ho, N. J. Ward, et D. J. Calkins, « TRPV1: a stress response protein in the central nervous system », Am. J. Neurodegener. Dis., vol. 1, no 1, p. 1‑14, avr. 2012.</ref> Depending on the target residu, the impact on the receptor will be different as various activation pathways are impacted. Phosphorylation improves the efficiency of the receptor and because it regulates the function, it is a target to treat [https://en.wikipedia.org/wiki/Hyperalgesia Hyperalgesia]. <ref name="Phosphorylation of TRPV1 S801 Contributes to Modality-Specific Hyperalgesia in Mice"> John Joseph, L. Qu, S. Wang, M. Kim, D. Bennett, J. Ro, M. J. Caterina and MK. Chung, Journal of Neuroscience 11 December 2019, 39 (50) 9954-9966. https://www.jneurosci.org/content/39/50/9954 (Consulté le: déc. 23, 2021). [En ligne].</ref>. PKA phosphorylates <scene name='86/868185/S502_t370/1'>T370 and S502</scene>, PKC and CaMKII phosphorylate <scene name='86/868185/Ser502_thr704/1'>S502 and T704</scene>.
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The phosphorylation of TRPV1 lead to an '''over-expression ''' of TRPV1 at the membrane surface.<ref>K. W. Ho, N. J. Ward, et D. J. Calkins, « TRPV1: a stress response protein in the central nervous system », Am. J. Neurodegener. Dis., vol. 1, no 1, p. 1‑14, avr. 2012.</ref> Moreover, phosphorylated TRPV1 would have a reduced channel opening threshold.<ref>G. Bhave et al., « Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) », Proc. Natl. Acad. Sci., vol. 100, no 21, p. 12480‑12485, oct. 2003, doi: 10.1073/pnas.2032100100.</ref>. As a result phosphorylated TRPV1 are more responsive to agonist and the resulting pain sensation is higher.
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PKA phosphorylates <scene name='86/868185/S502_t370/1'>T370 and S502</scene>, PKC and CaMKII phosphorylate <scene name='86/868185/Ser502_thr704/1'>S502 and T704</scene>.
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====Desensitization====
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A repeated exposure of TRPV1 to capsaicin fails to activate the receptor. It occurs by a Ca2+-dependent mechanism that leads to a '''desphosphorylation''' by the '''calcineurin''' [https://en.wikipedia.org/wiki/Phosphatase phosphatase] of the serine and threonine residues which have been previously phosphorylated by PKA (<scene name='86/868185/S502_t370/2'>S502 and T370</scene>). Thus, the decrease in TRPV1 phosphorylation diminish the sensitivity of the capsaicin channel and leads to a decrease in capsaicin's response by '''negative feedback'''.
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The '''over-stimulation''' of TRPV1 is followed by the nerve endings' death due to calcium overload, causing analgesia. <ref name="Integrating TRPV1 Receptor Function with Capsaicin Psychophysics">G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016</ref>
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== Implication of TRPV1 in the treatment of pain ==
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Capsaicin stimulates and desensitizes several receptors from the A(delta) and C fibers. This phenomenon will release inflammatory neuropeptides.
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Capsaicin assists the entry of Ca2+ in the neuron by a nonspecific membrane.
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TRPV1 can be activated by heat and voltage variation.
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This receptor exists under 3 different forms and ethanol is able to activate this receptor.
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In 2011 Qutenza (NeurogesX) patch containing 8% of capsaicin has been marketed in France and indicated in the [https://en.wikipedia.org/wiki/Neuropathic_pain neuropathic pain].
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The absorption through the skin of these creams generated partial desensitization of the nerve endings. This is the cause of a decrease in painful sensations.<ref name="TRPV1 dans les neuropathies douloureuses - Des modèles animaux aux perspectives thérapeutiques"> A. Danigo, L. Magy, et C. Demiot, « TRPV1 dans les neuropathies douloureuses - Des modèles animaux aux perspectives thérapeutiques », médecine/sciences, vol. 29, no 6‑7, Art. no 6‑7, juin 2013, doi: 10.1051/medsci/2013296012.</ref>
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[https://en.wikipedia.org/wiki/Capsazepine Capsazepine] is a synthetic competitive antagonist of this receptor which is currently used to study TRPV1 function.
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Many laboratories are conducting clinical studies on oral TRPV1 antagonists: [https://fr.wikipedia.org/wiki/GlaxoSmithKline GlaxoSmithKline ], [https://en.wikipedia.org/wiki/Amgen Amgen], [https://en.wikipedia.org/wiki/Merck_%26_Co. Merck]-Neurogen, [https://en.wikipedia.org/wiki/Abbott_Laboratories Abbott], [https://en.wikipedia.org/wiki/Eli_Lilly_and_Company Eli Lilly], [https://en.wikipedia.org/wiki/AstraZeneca AstraZeneca] and [https://en.wikipedia.org/wiki/Japan_Tobacco Japan Tobacco]. Nowadays at least seven orally active TRPV1 antagonist substances successfully went for clinical development and the laboratories cited before all completed phase I trials . However some of them have stopped their researches at phase II trials by unknown reason as GlaxoSmithKline
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with the antagonist SB-705498 or Lilly with the antagonist GRC 6211. <ref name="SB-705498"> The National Center for Advancing Translational Sciences «SB-705498 » , https://drugs.ncats.io/drug/T74V9O0Y2W, (Consulté le: déc. 29, 2021)</ref> <ref name="Further Clinical Trials in Osteoarthritis Pain Suspended for GRC 6211"> Calisha Myers, 24 oct. 2008, «Further Clinical Trials in Osteoarthritis Pain Suspended for GRC 6211 » , https://www.fiercebiotech.com/biotech/further-clinical-trials-osteoarthritis-pain-suspended-for-grc-6211, (Consulté le: déc. 29, 2021)</ref>
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The research on the antagonists of TRPV1 remains encouraging. <ref name="TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development"> A. Garami,E. Pakai,H. A. McDonald,R. M. Reilly,A. Gomtsyan,J. J. Corrigan,E. Pinter,D. X. D. Zhu,S. G. Lehto,N. R. Gavva,P. R. Kym,A. A. Romanovsky, 20 jan. 2018, «TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development » ,https://onlinelibrary.wiley.com/doi/full/10.1111/apha.13038
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, (Consulté le: déc. 29, 2021)</ref>
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
 
</StructureSection>
</StructureSection>
== References ==
== References ==
<references/>
<references/>

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This Sandbox is Reserved from 26/11/2020, through 26/11/2021 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1643 through Sandbox Reserved 1664.
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The Transient Receptor Potential cation channel subfamily V member 1 TRPV1

Structure of TRPV1 in complex with capsazepine, determined in lipid nano disc, capsazepine is a synthetic antagonist of capsaicin

Drag the structure with the mouse to rotate

References

  1. ↑ 1.0 1.1 1.2 Wikipedia contributors. (2020, december 21). TRPV1. Wikipedia. https://en.wikipedia.org/wiki/TRPV1 (Consulted the: dec. 28, 2020). [Online].
  2. ↑ 2.0 2.1 A. Danigo, L. Magy et C. Demiot , Med Sci (Paris) Volume 29, Number 6-7, Juin–Juillet 2013, p. 597-606. TRPV1 dans les neuropathies douloureuses, https://www.medecinesciences.org/en/articles/medsci/full_html/2013/08/medsci2013296-7p597/medsci2013296-7p597.html, (Consulted the : dec. 23, 2021). [Online].
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Liao, M., Cao, E., Julius, D., & Cheng, Y. (2013b). Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature, 504(7478), 107‑112. https://doi.org/10.1038/nature12822(consulté le déc. 28, 2020)
  4. ↑ T. Rosenbaum et S. A. Simon, « TRPV1 Receptors and Signal Transduction », in TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades, W. B. Liedtke et S. Heller, Éd. Boca Raton (FL): CRC Press/Taylor & Francis, 2007
  5. ↑ 5.0 5.1 5.2 5.3 5.4 G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016
  6. ↑ R. Kumar, A. Hazan, A. Basu, N. Zalcman, H. Matzner, et A. Priel, « Tyrosine Residue in the TRPV1 Vanilloid Binding Pocket Regulates Deactivation Kinetics », J. Biol. Chem., vol. 291, no 26, p. 13855‑13863, juin 2016, doi: 10.1074/jbc.M116.726372.
  7. ↑ X. Yao, H.-Y. Kwan, et Y. Huang, « Regulation of TRP Channels by Phosphorylation », Neurosignals, vol. 14, no 6, p. 273‑280, 2005, doi: 10.1159/000093042
  8. ↑ F. Yang et J. Zheng, « Understand spiciness: mechanism of TRPV1 channel activation by capsaicin », Protein Cell, vol. 8, no 3, p. 169‑177, mars 2017, doi: 10.1007/s13238-016-0353-7.
  9. ↑ F. Yang et al., « Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel », Nat. Chem. Biol., vol. 11, no 7, Art. no 7, juill. 2015, doi: 10.1038/nchembio.1835.
  10. ↑ F. Yang et al., « The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel », Nat. Commun., vol. 9, no 1, Art. no 1, juill. 2018, doi: 10.1038/s41467-018-05339-6.
  11. ↑ 11.0 11.1 K. Elokely et al., « Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin », Proc. Natl. Acad. Sci., vol. 113, no 2, p. E137‑E145, janv. 2016, doi:10.1073/pnas.1517288113.
  12. ↑ John Joseph, L. Qu, S. Wang, M. Kim, D. Bennett, J. Ro, M. J. Caterina and MK. Chung, Journal of Neuroscience 11 December 2019, 39 (50) 9954-9966. https://www.jneurosci.org/content/39/50/9954 (Consulté le: déc. 23, 2021). [En ligne].
  13. ↑ K. W. Ho, N. J. Ward, et D. J. Calkins, « TRPV1: a stress response protein in the central nervous system », Am. J. Neurodegener. Dis., vol. 1, no 1, p. 1‑14, avr. 2012.
  14. ↑ G. Bhave et al., « Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) », Proc. Natl. Acad. Sci., vol. 100, no 21, p. 12480‑12485, oct. 2003, doi: 10.1073/pnas.2032100100.
  15. ↑ A. Danigo, L. Magy, et C. Demiot, « TRPV1 dans les neuropathies douloureuses - Des modèles animaux aux perspectives thérapeutiques », médecine/sciences, vol. 29, no 6‑7, Art. no 6‑7, juin 2013, doi: 10.1051/medsci/2013296012.
  16. ↑ The National Center for Advancing Translational Sciences «SB-705498 » , https://drugs.ncats.io/drug/T74V9O0Y2W, (Consulté le: déc. 29, 2021)
  17. ↑ Calisha Myers, 24 oct. 2008, «Further Clinical Trials in Osteoarthritis Pain Suspended for GRC 6211 » , https://www.fiercebiotech.com/biotech/further-clinical-trials-osteoarthritis-pain-suspended-for-grc-6211, (Consulté le: déc. 29, 2021)
  18. ↑ A. Garami,E. Pakai,H. A. McDonald,R. M. Reilly,A. Gomtsyan,J. J. Corrigan,E. Pinter,D. X. D. Zhu,S. G. Lehto,N. R. Gavva,P. R. Kym,A. A. Romanovsky, 20 jan. 2018, «TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development » ,https://onlinelibrary.wiley.com/doi/full/10.1111/apha.13038 , (Consulté le: déc. 29, 2021)
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