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== Introduction == | == Introduction == | ||
[(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, which 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 / channels: TRPVs. | [(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, which 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 / channels: TRPVs. | ||
This receptor is expressed by sensory neurons of the dorsal and trigeminal spinal ganglia which secrete CGRP (calcitonin gene-related peptide) and substance P, two neuropeptides. <ref>« TRPV1 », Wikipédia. sept. 09, 2020, Consulté le: déc. 28, 2020. [En ligne]. Disponible sur: https://fr.wikipedia.org/w/index.php?title=TRPV1&oldid=174570512.</ref> | This receptor is expressed by sensory neurons of the dorsal and trigeminal spinal ganglia which secrete CGRP (calcitonin gene-related peptide) and substance P, two neuropeptides.<ref>« TRPV1 », Wikipédia. sept. 09, 2020, Consulté le: déc. 28, 2020. [En ligne]. Disponible sur: https://fr.wikipedia.org/w/index.php?title=TRPV1&oldid=174570512.</ref> | ||
== Structure of TRPV1 == | == Structure of TRPV1 == | ||
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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> | 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> | ||
The N-terminal region has 6 repeats of [https://en.wikipedia.org/wiki/Ankyrin ankyrin]. N-terminal region is followed by a linker domain.<ref>« Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ».https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)</ref> | The N-terminal region has 6 repeats of [https://en.wikipedia.org/wiki/Ankyrin ankyrin]. N-terminal region is followed by a linker domain.<ref>« Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ».https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)</ref><ref>G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016</ref> | ||
<ref>G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016</ref> | |||
The transmembrane region is composed of six transmembrane a helices (S1-S6). S4 and S5 are separated by a linker parallel to the membrane. A small hydrophobic domain beetween S5 and S6 with a re-entrant loop constitutes the pore allowing the passage of ions through the TRPV1 receptor.<ref>« Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020).</ref> | The transmembrane region is composed of six transmembrane a helices (S1-S6). S4 and S5 are separated by a linker parallel to the membrane. A small hydrophobic domain beetween S5 and S6 with a re-entrant loop constitutes the pore allowing the passage of ions through the TRPV1 receptor.<ref>« Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020).</ref><ref>« TRPV1 », Wikipédia. sept. 09, 2020, Consulté le: déc. 28, 2020. [En ligne]. Disponible sur: https://fr.wikipedia.org/w/index.php?title=TRPV1&oldid=174570512.</ref> | ||
<ref>« TRPV1 », Wikipédia. sept. 09, 2020, Consulté le: déc. 28, 2020. [En ligne]. Disponible sur: https://fr.wikipedia.org/w/index.php?title=TRPV1&oldid=174570512.</ref> | |||
S1,S2,S3 helices contain aromatic side chain (S1 : Y441,Y444,Y555 S2: F488 S3 : F516)<ref>« Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)</ref> | S1,S2,S3 helices contain aromatic side chain (S1 : Y441,Y444,Y555 S2: F488 S3 : F516).<ref>« Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)</ref> | ||
‘’’Threonin’’’ residu (T550) and ‘’’tyrosin’’’ residu (Y511) 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> | ‘’’Threonin’’’ residu (T550) and ‘’’tyrosin’’’ residu (Y511) 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> | ||
The S6 domain links the receptor to the C-terminal domain of TRPV1.The C-terminal is made of 150 amino acids and it contains ‘’’TRP domain’’’<ref>G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016.</ref> | The S6 domain links the receptor to the C-terminal domain of TRPV1.The C-terminal is made of 150 amino acids and it contains ‘’’TRP domain’’’.<ref>G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016.</ref> | ||
The TRP domain is made of 23-25 aminoacids with a alpha helical structure, it is found in many TRP family members.<ref>« Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)</ref> | The TRP domain is made of 23-25 aminoacids with a alpha helical structure, it is found in many TRP family members.<ref>« Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)</ref> | ||
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Capsaicin is an active compound in chili. | Capsaicin is an active compound in chili. | ||
TRPV1 receptor has a ‘’’capsaicin-binding pocket’’’ formed by S3,S4 and S4-S5 linker. The capsaicin-binding pocket is surrounded by the residues Y511, S512,T550.<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> | |||
Bound [https://en.wikipedia.org/wiki/Capsaicin capsaicin] is oriented in a « tail-up, head down » configuration. In this configuration the vanillyl and amide groups of capsaicin form specific interactions with TRPV1,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> | Bound [https://en.wikipedia.org/wiki/Capsaicin capsaicin] is oriented in a « tail-up, head down » configuration. In this configuration the vanillyl and amide groups of capsaicin form specific interactions with TRPV1,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 (Y511, S513), on the S4-S5 linker (E571) and on the S6 helix (T671). The amid group of capsaicin binds the S4 helix (T551).<ref>G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016.</ref> | The capsaicin cycle binds via hydrogen bounds to amino acids on the S3 helix (Y511, S513), on the S4-S5 linker (E571) and on the S6 helix (T671). The amid group of capsaicin binds the S4 helix (T551).<ref>G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016.</ref> | ||
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> | 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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PKC phosphorlyates TRPV1 at S800,S502, PKA phosphorylates TRPV1 at S116. | PKC phosphorlyates TRPV1 at S800,S502, PKA phosphorylates TRPV1 at S116. | ||
The phosphorylation of TRPV1 lead to an increase in the 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> | The phosphorylation of TRPV1 lead to an increase in the 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> | 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 because they are overexpressed and the same quantity of agonist leads to a better openings of ion channels. | As a result phosphorylated TRPV1 are more responsive to agonist because they are overexpressed and the same quantity of agonist leads to a better openings of ion channels. | ||
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In 2011 Qutenza (NeurogesX) patch containing 8% of capsaicin has been markered in France and indicated in the ‘’’treatment of non-diabetic neuropathic pain’’’. | In 2011 Qutenza (NeurogesX) patch containing 8% of capsaicin has been markered in France and indicated in the ‘’’treatment of non-diabetic neuropathic pain’’’. | ||
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>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> | 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>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> | ||
Many laboratories are conducting clinical studies on oral TRPV1 antagonists: GlaxoSmithKline, Amgen, Merk-Neurogen, Abbot, Eli-Lilly-Glenmark, AstraZeneca and Japan Tobacco. The major problem with these pain relievers is the [https://en.wikipedia.org/wiki/Hyperthermia hyperthermia] generated in humans by AMG517 (Amgen lab) and ABT-102 (Abbott lab). These effects caused these studies to be stopped in phase I.<ref>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> | Many laboratories are conducting clinical studies on oral TRPV1 antagonists: GlaxoSmithKline, Amgen, Merk-Neurogen, Abbot, Eli-Lilly-Glenmark, AstraZeneca and Japan Tobacco. The major problem with these pain relievers is the [https://en.wikipedia.org/wiki/Hyperthermia hyperthermia] generated in humans by AMG517 (Amgen lab) and ABT-102 (Abbott lab). These effects caused these studies to be stopped in phase I.<ref>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> | ||
