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From Proteopedia
(Difference between revisions)
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TRPV1 are ‘’’tetrameric’’’ channel type receptors. The four subunits from a symmetry plane around a pore allowing the passage of ions. | TRPV1 are ‘’’tetrameric’’’ channel type receptors. The four subunits from a symmetry plane around a pore allowing the passage of ions. | ||
- | Each TRPV1 subunits are 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. | + | Each TRPV1 subunits are 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>« 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> |
- | TRPV1 exists in two states : the open state and the closed state | + | 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 | + | 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. | + | 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) | + | 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. | + | ‘’’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’’’ | + | 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 | + | 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> |
TRP domain is necessary for the formation of tetrameric TRPV1. | TRP domain is necessary for the formation of tetrameric TRPV1. | ||
- | 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]. | + | 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> |
== Relation structure-function == | == Relation structure-function == | ||
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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. | + | 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 | + | 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> |
- | + | 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) | + | |
- | Capsaicin maintains TRPV1 in an open state by «pull and contact» interactions. A conformational change wave spread over the whole pore | + | 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> |
- | This leads to the massive enter of Ca2+ and Na+ in the cytoplasm of the nerve fiber and to the depolarization of the nerve fiber. When depolarization reach a theshold value it triggers the generation of an [https://en.wikipedia.org/wiki/Action_potential action potential] causing a painful sensation. | + | This leads to the massive enter of Ca2+ and Na+ in the cytoplasm of the nerve fiber and to the depolarization of the nerve fiber. When depolarization reach a theshold value it triggers the generation of an [https://en.wikipedia.org/wiki/Action_potential action potential] causing a painful sensation.<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> |
#Résinifératoxine (RTX) | #Résinifératoxine (RTX) | ||
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However, the orientation of L515 and M547 makes this region of the vanilloid pocket narrow, which considerably limits the nature of the fragments tolerated. | However, the orientation of L515 and M547 makes this region of the vanilloid pocket narrow, which considerably limits the nature of the fragments tolerated. | ||
- | The aromatic is located deeper in the sub-pocket near Y511 and is oriented almost parallel to the aromatic side chain of Y511, so it establishes a strong interaction π-π. The aromatic hydroxyl and methoxy groups of the RTX form strong hydrogen bonds with E570, R557 and S512. The ester group is linked to Y511 and T550 by hydrogen bonds. <ref>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> | + | The aromatic is located deeper in the sub-pocket near Y511 and is oriented almost parallel to the aromatic side chain of Y511, so it establishes a strong interaction π-π. The aromatic hydroxyl and methoxy groups of the RTX form strong hydrogen bonds with E570, R557 and S512. The ester group is linked to Y511 and T550 by hydrogen bonds.<ref>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> |
=== Regulation === | === Regulation === | ||
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’’Phosphorylation’’’ of the TRPV1 receptor leads to its sensitization. | ’’Phosphorylation’’’ of the TRPV1 receptor leads to its sensitization. | ||
- | Phosphorylations occurs on multiple phosphorylation sites at both N-terminal and C-terminal sites of TRPV1 by [https://en.wikipedia.org/wiki/Kinase kinases]. Phosphorylations are either caused by PKC (IP3 signalling), by PKA (AMPc signalling) or by CamKII an PI3K. | + | Phosphorylations occurs on multiple phosphorylation sites at both N-terminal and C-terminal sites of TRPV1 by [https://en.wikipedia.org/wiki/Kinase kinases]. Phosphorylations are either caused by PKC (IP3 signalling), by PKA (AMPc signalling) or by CamKII an PI3K.<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> |
<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> | ||
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 | + | 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 | + | 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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== Implication of TRPV1 in the treatment of pain == | == Implication of TRPV1 in the treatment of 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’’’. | 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. | + | 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 | + | 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> |
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The Transient Receptor Potential cation channel subfamily V member 1 TRPV1
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References
- ↑ « 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.
- ↑ « Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)
- ↑ « Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)
- ↑ 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
- ↑ « Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ».https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)
- ↑ G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016
- ↑ « Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020).
- ↑ « 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.
- ↑ « Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)
- ↑ 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.
- ↑ G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016.
- ↑ « Structure of the TRPV1 ion channel determined by electron cryo-microscopy | Nature ». https://www.nature.com/articles/nature12822#Fig3 (consulté le déc. 28, 2020)
- ↑ 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
- ↑ 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.
- ↑ 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.
- ↑ G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016.
- ↑ 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.
- ↑ « 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
- ↑ 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.
- ↑ 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.
- ↑ G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.