Tags

Type your tag names separated by a space and hit enter

Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain.
Biochemistry. 2004 Mar 09; 43(9):2501-11.B

Abstract

The capsaicin receptor (TRPV1) is a nonselective cation channel that is activated in nociceptors by several painful stimuli, and hence TRPV1 antagonists could represent a novel class of analgesic compounds. Resiniferatoxin (RTX), a potent agonist of TRPV1, and iodoresiniferatoxin (I-RTX), a potent antagonist of TRPV1, both bind with higher affinity to the rat TRPV1 (rTRPV1) than the human (hTRPV1) isoform. To identify the structural features responsible for this difference in affinity, [(3)H]RTX binding to chimeras between hTRPV1 and rTRPV1 was characterized. The "sensor" region within the transmembrane domain (S1-S4) was found to determine [(3)H]RTX binding affinity. All 16 different residues in this region were systematically substituted in hTRPV1 with rTRPV1 residues. A single mutation in the S4 membrane domain of hTRPV1, L547M, caused a 30-fold increase in [(3)H]RTX affinity whereas the inverse mutation in rTRPV1, M547L, caused a 30-fold decrease in affinity for [(3)H]RTX, and several other agonists and antagonists were similarly affected by these mutations. TRPV1 channels with mutations at position 547 were expressed in oocytes, and the relative response to RTX followed a pattern similar to that seen with [(3)H]RTX binding. These data suggest a model where Met-547 in the S4 domain of TRPV1 forms a binding pocket with Tyr-511 in the S3 domain. This model places RTX near the sensor domain thought to move during the gating process and should help to guide further work designed to understand the gating mechanisms of TRPV1 channels based on comparisons between the agonist RTX and the related competitive antagonist I-RTX.

Authors+Show Affiliations

Department of Ion Channels, Merck Research Laboratories, Rahway, New Jersey 07065, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14992587

Citation

Chou, Margaret Z., et al. "Resiniferatoxin Binds to the Capsaicin Receptor (TRPV1) Near the Extracellular Side of the S4 Transmembrane Domain." Biochemistry, vol. 43, no. 9, 2004, pp. 2501-11.
Chou MZ, Mtui T, Gao YD, et al. Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain. Biochemistry. 2004;43(9):2501-11.
Chou, M. Z., Mtui, T., Gao, Y. D., Kohler, M., & Middleton, R. E. (2004). Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain. Biochemistry, 43(9), 2501-11.
Chou MZ, et al. Resiniferatoxin Binds to the Capsaicin Receptor (TRPV1) Near the Extracellular Side of the S4 Transmembrane Domain. Biochemistry. 2004 Mar 9;43(9):2501-11. PubMed PMID: 14992587.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain. AU - Chou,Margaret Z, AU - Mtui,Tecla, AU - Gao,Ying-Duo, AU - Kohler,Martin, AU - Middleton,Richard E, PY - 2004/3/3/pubmed PY - 2004/6/30/medline PY - 2004/3/3/entrez SP - 2501 EP - 11 JF - Biochemistry JO - Biochemistry VL - 43 IS - 9 N2 - The capsaicin receptor (TRPV1) is a nonselective cation channel that is activated in nociceptors by several painful stimuli, and hence TRPV1 antagonists could represent a novel class of analgesic compounds. Resiniferatoxin (RTX), a potent agonist of TRPV1, and iodoresiniferatoxin (I-RTX), a potent antagonist of TRPV1, both bind with higher affinity to the rat TRPV1 (rTRPV1) than the human (hTRPV1) isoform. To identify the structural features responsible for this difference in affinity, [(3)H]RTX binding to chimeras between hTRPV1 and rTRPV1 was characterized. The "sensor" region within the transmembrane domain (S1-S4) was found to determine [(3)H]RTX binding affinity. All 16 different residues in this region were systematically substituted in hTRPV1 with rTRPV1 residues. A single mutation in the S4 membrane domain of hTRPV1, L547M, caused a 30-fold increase in [(3)H]RTX affinity whereas the inverse mutation in rTRPV1, M547L, caused a 30-fold decrease in affinity for [(3)H]RTX, and several other agonists and antagonists were similarly affected by these mutations. TRPV1 channels with mutations at position 547 were expressed in oocytes, and the relative response to RTX followed a pattern similar to that seen with [(3)H]RTX binding. These data suggest a model where Met-547 in the S4 domain of TRPV1 forms a binding pocket with Tyr-511 in the S3 domain. This model places RTX near the sensor domain thought to move during the gating process and should help to guide further work designed to understand the gating mechanisms of TRPV1 channels based on comparisons between the agonist RTX and the related competitive antagonist I-RTX. SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/14992587/Resiniferatoxin_binds_to_the_capsaicin_receptor__TRPV1__near_the_extracellular_side_of_the_S4_transmembrane_domain_ L2 - https://dx.doi.org/10.1021/bi035981h DB - PRIME DP - Unbound Medicine ER -