| Structural highlights
5irz is a 4 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 5irx, 5is0 |
| Gene: | Trpv1, Vr1, Vr1l (Buffalo rat) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[TRPV1_RAT] Receptor-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. May be involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Activation by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. Can be activated by endogenous compounds, including 12-hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
When integral membrane proteins are visualized in detergents or other artificial systems, an important layer of information is lost regarding lipid interactions and their effects on protein structure. This is especially relevant to proteins for which lipids have both structural and regulatory roles. Here we demonstrate the power of combining electron cryo-microscopy with lipid nanodisc technology to ascertain the structure of the rat TRPV1 ion channel in a native bilayer environment. Using this approach, we determined the locations of annular and regulatory lipids and showed that specific phospholipid interactions enhance binding of a spider toxin to TRPV1 through formation of a tripartite complex. Furthermore, phosphatidylinositol lipids occupy the binding site for capsaicin and other vanilloid ligands, suggesting a mechanism whereby chemical or thermal stimuli elicit channel activation by promoting the release of bioactive lipids from a critical allosteric regulatory site.
TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action.,Gao Y, Cao E, Julius D, Cheng Y Nature. 2016 May 18;534(7607):347-51. doi: 10.1038/nature17964. PMID:27281200[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997 Oct 23;389(6653):816-24. PMID:9349813 doi:http://dx.doi.org/10.1038/39807
- ↑ Schumacher MA, Moff I, Sudanagunta SP, Levine JD. Molecular cloning of an N-terminal splice variant of the capsaicin receptor. Loss of N-terminal domain suggests functional divergence among capsaicin receptor subtypes. J Biol Chem. 2000 Jan 28;275(4):2756-62. PMID:10644739
- ↑ Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by protein kinase C. Nature. 2000 Dec 21-28;408(6815):985-90. PMID:11140687 doi:http://dx.doi.org/10.1038/35050121
- ↑ Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature. 2001 Jun 21;411(6840):957-62. PMID:11418861 doi:http://dx.doi.org/10.1038/35082088
- ↑ Olah Z, Karai L, Iadarola MJ. Protein kinase C(alpha) is required for vanilloid receptor 1 activation. Evidence for multiple signaling pathways. J Biol Chem. 2002 Sep 20;277(38):35752-9. Epub 2002 Jul 2. PMID:12095983 doi:http://dx.doi.org/10.1074/jbc.M201551200
- ↑ Bhave G, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW 4th. cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron. 2002 Aug 15;35(4):721-31. PMID:12194871
- ↑ Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M. Structural determinant of TRPV1 desensitization interacts with calmodulin. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):8002-6. Epub 2003 Jun 13. PMID:12808128 doi:http://dx.doi.org/10.1073/pnas.1337252100
- ↑ Bhave G, Hu HJ, Glauner KS, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW 4th. Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12480-5. Epub 2003 Oct 1. PMID:14523239 doi:http://dx.doi.org/10.1073/pnas.2032100100
- ↑ Prescott ED, Julius D. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science. 2003 May 23;300(5623):1284-8. PMID:12764195 doi:http://dx.doi.org/10.1126/science.1083646
- ↑ Jung J, Shin JS, Lee SY, Hwang SW, Koo J, Cho H, Oh U. Phosphorylation of vanilloid receptor 1 by Ca2+/calmodulin-dependent kinase II regulates its vanilloid binding. J Biol Chem. 2004 Feb 20;279(8):7048-54. Epub 2003 Nov 20. PMID:14630912 doi:http://dx.doi.org/10.1074/jbc.M311448200
- ↑ Hellwig N, Plant TD, Janson W, Schafer M, Schultz G, Schaefer M. TRPV1 acts as proton channel to induce acidification in nociceptive neurons. J Biol Chem. 2004 Aug 13;279(33):34553-61. Epub 2004 Jun 1. PMID:15173182 doi:http://dx.doi.org/10.1074/jbc.M402966200
- ↑ Chavez AE, Chiu CQ, Castillo PE. TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nat Neurosci. 2010 Dec;13(12):1511-8. doi: 10.1038/nn.2684. Epub 2010 Nov 14. PMID:21076423 doi:http://dx.doi.org/10.1038/nn.2684
- ↑ Gao Y, Cao E, Julius D, Cheng Y. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature. 2016 May 18;534(7607):347-51. doi: 10.1038/nature17964. PMID:27281200 doi:http://dx.doi.org/10.1038/nature17964
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