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The Transient Receptor Potential cation channel subfamily V member 1 TRPV1

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Structure of TRPV1 in complex with capsazepine, determined in lipid nanodisc

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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 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.TRPV1 is implicated in nociception, its activation by heat or by chemical substances leads to a painful sensation.^[1]

Structure of TRPV1

The TRPV1 receptor is a transmembrane protein receptor. It is made up of 839 amino acids. It’s molecular weight is 94 938Da.^[2] TRPV1 exists in two states : the open state and the closed state.^[3] 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.^[2]

The N-terminal region has 6 repeats of ankyrin.^[2]^[4]

The transmembrane region is composed of six transmembrane a helices (S1,S2,S3,S4,S5,S6). S1,S2 and S3 helices contain aromatic side chain (S1 : Y441,Y444,Y555 S2: F488 S3 : F516).^[2] 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.^[1]^[2]

Threonin residue (T550) and Tyrosin residue (Y511) located on the fifth and the third transmembrane helices are very conserved. Threonin 550 and Aspargin 511 are implicated in TRPV1 activation by vanilloids and in pain sensation.^[5]

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.^[4].The TRP domain is made of 23-25 aminoacids with a alpha helical structure, it is found in many TRP family members.^[2] 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 kinases and phosphatases.^[6]

Relation structure-function

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. The state of the channel is modulated by two types of molecules: agents that promote its opening of the channel, called agonists, and agents that induce its closure or prevent its opening, called antagonists.

Activators

Capsaicin

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.^[7]

Bound 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.^[8]

The capsaicin cycle binds via hydrogen bounds to amino acids on the S3 helix (Y511), on the S4-S5 linker and on the S6 helix (T671). The amid group of capsaicin binds the S4 helix.Cite error: Closing </ref> missing for <ref> tag. 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 action potential causing a painful sensation.^[1]

Resiniferatoxin (RTX)

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. Stimulation by resiniferatoxin makes this ion channel permeable to cations, especially calcium.

The pocket size characteristics of the TRPV1-RTX allow the installation of large structures such as the RTX : The sub-pocket near Y511 is shallow in the TRPV1-RTX because Y511 and E570 are close and I569 is oriented towards the vanilloid pocket.

The sub-pocket near L669, V583, and F587 is wide due to the projection of these amino acids out of the vanilloid pocket. This sub-pocket accommodates the diterpene group of the RTX. 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 part of resiniferatoxin 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.^[9]

Regulation

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 kinases. Phosphorylations are either caused by PKC (IP3 signalling), by PKA (AMPc signalling) or by CamKII.^[10]Cite error: Closing </ref> missing for <ref> tag. Moreover, phosphorylated TRPV1 would have a reduced channel opening threshold.^[11]. As a result phosphorylated TRPV1 are more responsive to agonist because they are overexpressed and because the same quantity of agonist leads to a better openings of ion channels.

Desensitization

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 phosphatase of the serine and threonine residues which have been previously phosphorylated by PKA. 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. The influx of cations causes the depolarisation of the neuron, which transmits signals like those that would be transmitted if the innervated tissue were burnt or damaged. This stimulation is followed by desensitisation and analgesia, partly because the nerve endings die due to calcium overload.

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. 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.^[12]

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 hyperthermia generated in humans by AMG517 (Amgen lab) and ABT-102 (Abbott lab). These effects caused these studies to be stopped in phase I.^[12]

↑ ^1.0 ^1.1 ^1.2 Wikipedia contributors. (2020b, décembre 21). TRPV1. Wikipedia. https://en.wikipedia.org/wiki/TRPV1 (Consulté le: déc. 28, 2020). [En ligne].
↑ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 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)
↑ 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
↑ ^4.0 ^4.1 G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016
↑ 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.
↑ 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.
↑ 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. 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.
↑ ^12.0 ^12.1 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.

References

[TRPV1-1] 1.0 ^1.1 ^1.2 Wikipedia contributors. (2020b, décembre 21). TRPV1. Wikipedia. https://en.wikipedia.org/wiki/TRPV1 (Consulté le: déc. 28, 2020). [En ligne].

[Structure_of_the_TRPV1_ion_channel_determined_by_electron_cryo-microscopy-2] 2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 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)

[3] 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

[Integrating_TRPV1_Receptor_Function_with_Capsaicin_Psychophysics-4] 4.0 ^4.1 G. Smutzer et R. K. Devassy, « Integrating TRPV1 Receptor Function with Capsaicin Psychophysics », Advances in Pharmacological Sciences, janv. 14, 2016

[5] 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.

[6] 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

[7] 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.

[8] 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.

[9] 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.

[10] 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.

[11] 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.

[TRPV1_dans_les_neuropathies_douloureuses_-_Des_modèles_animaux_aux_perspectives_thérapeutiques-12] 12.0 ^12.1 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.

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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>
 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.<ref name="Structure of the TRPV1 ion channel determined by electron cryo-microscopy"/>
+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 name="Structure of the TRPV1 ion channel determined by electron cryo-microscopy"/>
 The N-terminal 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>
 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/Aromatic_residues_of_s1_s2_s3/1'>S1 : Y441,Y444,Y555 S2: F488 S3 : F516</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"/>
-'''Threonin''' residu (<scene name='86/868185/T550/1'>T550</scene>) and '''Tyrosin''' reside (<scene name='86/868185/Y511/2'>Y511</scene>) located on the fifth and the third transmembrane helices are very conserved. Threonin 550 and Aspargin 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''' 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 Aspargin 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 '''<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.

Sandbox Reserved 1652: Difference between revisions

Revision as of 14:31, 8 January 2021

The Transient Receptor Potential cation channel subfamily V member 1 TRPV1

Contents

Introduction

Structure of TRPV1

Relation structure-function

Activators

Capsaicin

Resiniferatoxin (RTX)

Regulation

Sensitization

Desensitization

Implication of TRPV1 in the treatment of pain

References

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