Sandbox Reserved 1652: Difference between revisions

From Proteopedia
Jump to navigationJump to search
← Older editNewer edit →
No edit summary
No edit summary
Line 37: Line 37:
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>
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>
   
   
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.<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 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>
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">
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">
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>.  


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.<ref name="TRPV1"/>
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"/>


====Resiniferatoxin (RTX)====
====Resiniferatoxin (RTX)====
Line 61: Line 61:
====Sensitization====
====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''' ([https://en.wikipedia.org/wiki/Inositol_trisphosphate IP3 signalling]), by '''PKA''' ([https://fr.wikipedia.org/wiki/Adénylate_cyclase AMPc signalling]), or by '''CamKII'''.<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 name="Integrating TRPV1 Receptor Function with Capsaicin Psychophysics">.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>.  
'''Phosphorylation''' of the TRPV1 receptor leads to its sensitization. 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'''.<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 name="Integrating TRPV1 Receptor Function with Capsaicin Psychophysics">.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>.  
  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>. 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.
  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 '''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.


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>.  
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>.  
Line 69: Line 69:


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. 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'''.
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. 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.
The '''over-stimulation''' of TRPV1 is followed by the nerve endings' death due to calcium overload, causing analgesia.  


== Implication of TRPV1 in the treatment of pain ==
== Implication of TRPV1 in the treatment of pain ==
Line 76: Line 76:
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>
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>


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 name="TRPV1 dans les neuropathies douloureuses - Des modèles animaux aux perspectives thérapeutiques"/>
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. These effects caused these studies to be stopped in phase I.<ref name="TRPV1 dans les neuropathies douloureuses - Des modèles animaux aux perspectives thérapeutiques"/>




Retrieved from "https://proteopedia.org/Sandbox_Reserved_1652"