Resiniferatoxin‐type phorboid vanilloids display capsaicin‐like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1
Although the cloned rat vanilloid receptor VR1 appears to account for both receptor binding and calcium uptake, the identification of vanilloids selective for one or the other response is of importance because these ligands may induce distinct patterns of biological activities. Phorbol 12,13‐didecan...
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| Veröffentlicht in: | British journal of pharmacology 1999-09, Vol.128 (2), p.428-434 |
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| creator | Szallasi, A Szabó, T Bíró, T Modarres, S Blumberg, P M Krause, J E Cortright, D N Appendino, G |
| description | Although the cloned rat vanilloid receptor VR1 appears to account for both receptor binding and calcium uptake, the identification of vanilloids selective for one or the other response is of importance because these ligands may induce distinct patterns of biological activities.
Phorbol 12,13‐didecanoate 20‐homovanillate (PDDHV) evoked 45Ca2+‐uptake by rat dorsal root ganglion neurons (expressing native vanilloid receptors) in culture with an EC50 of 70 nM but inhibited [3H]‐resiniferatoxin (RTX) binding to rat dorsal root ganglion membranes with a much lower potency (Ki>10,000 nM). This difference in potencies represents a more than 100 fold selectivity for capsaicin‐type pharmacology.
45Ca2+ influx by PDDHV was fully inhibited by the competitive vanilloid receptor antagonist capsazepine, consistent with the calcium uptake occurring via vanilloid receptors.
PDDHV induced calcium mobilization in CHO cells transfected with the cloned rat vanilloid receptor VR1 with an EC50 of 125 nM and inhibited [3H]‐RTX binding to these cells with an estimated Ki of 10,000 nM. By contrast, PDDHV failed to evoke a measurable calcium response in non‐transfected CHO cells, confirming its action through VR1.
We conclude that PDDHV is two orders of magnitude more potent for inducing calcium uptake than for inhibiting RTX binding at vanilloid receptors, making this novel vanilloid a ligand selective for capsaicin‐type pharmacology. These results emphasize the importance of monitoring multiple endpoints for evaluation of vanilloid receptor structure‐activity relations. Furthermore, PDDHV now provides a tool to explore the biological correlates of capsaicin‐type vanilloid pharmacology.
British Journal of Pharmacology (1999) 128, 428–434; doi:10.1038/sj.bjp.0702810 |
| doi_str_mv | 10.1038/sj.bjp.0702810 |
| format | Article |
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Phorbol 12,13‐didecanoate 20‐homovanillate (PDDHV) evoked 45Ca2+‐uptake by rat dorsal root ganglion neurons (expressing native vanilloid receptors) in culture with an EC50 of 70 nM but inhibited [3H]‐resiniferatoxin (RTX) binding to rat dorsal root ganglion membranes with a much lower potency (Ki>10,000 nM). This difference in potencies represents a more than 100 fold selectivity for capsaicin‐type pharmacology.
45Ca2+ influx by PDDHV was fully inhibited by the competitive vanilloid receptor antagonist capsazepine, consistent with the calcium uptake occurring via vanilloid receptors.
PDDHV induced calcium mobilization in CHO cells transfected with the cloned rat vanilloid receptor VR1 with an EC50 of 125 nM and inhibited [3H]‐RTX binding to these cells with an estimated Ki of 10,000 nM. By contrast, PDDHV failed to evoke a measurable calcium response in non‐transfected CHO cells, confirming its action through VR1.
We conclude that PDDHV is two orders of magnitude more potent for inducing calcium uptake than for inhibiting RTX binding at vanilloid receptors, making this novel vanilloid a ligand selective for capsaicin‐type pharmacology. These results emphasize the importance of monitoring multiple endpoints for evaluation of vanilloid receptor structure‐activity relations. Furthermore, PDDHV now provides a tool to explore the biological correlates of capsaicin‐type vanilloid pharmacology.
British Journal of Pharmacology (1999) 128, 428–434; doi:10.1038/sj.bjp.0702810</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0702810</identifier><identifier>PMID: 10510454</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>[3H]‐resiniferatoxin binding ; Animals ; Calcium - metabolism ; capsaicin ; Capsaicin - pharmacology ; capsaicin‐type vanilloid pharmacology ; Cell Membrane - metabolism ; CHO Cells ; Cloning, Molecular ; Cricetinae ; Diterpenes - pharmacology ; DNA, Complementary - biosynthesis ; DNA, Complementary - genetics ; Female ; Fluorescent Dyes ; Ganglia, Spinal - cytology ; Ganglia, Spinal - drug effects ; native vanilloid receptors ; Neurotoxins - pharmacology ; phorboid vanilloids ; Phorbol 12,13‐didecanoate 20‐homovanillate ; Rats ; Rats, Sprague-Dawley ; Receptors, Drug - drug effects ; Receptors, Drug - genetics ; vanilloid receptor subtype 1 (VR1) ; VR1‐transfected CHO cells</subject><ispartof>British journal of pharmacology, 1999-09, Vol.128 (2), p.428-434</ispartof><rights>1999 British Pharmacological Society</rights><rights>Copyright 1999, Nature Publishing Group 1999 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4550-c081f299392a8bc2ca733c5d5852a10f539e80d1b54f87fd965aa6157f1788353</citedby><cites>FETCH-LOGICAL-c4550-c081f299392a8bc2ca733c5d5852a10f539e80d1b54f87fd965aa6157f1788353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571651/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571651/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10510454$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Szallasi, A</creatorcontrib><creatorcontrib>Szabó, T</creatorcontrib><creatorcontrib>Bíró, T</creatorcontrib><creatorcontrib>Modarres, S</creatorcontrib><creatorcontrib>Blumberg, P M</creatorcontrib><creatorcontrib>Krause, J E</creatorcontrib><creatorcontrib>Cortright, D N</creatorcontrib><creatorcontrib>Appendino, G</creatorcontrib><title>Resiniferatoxin‐type phorboid vanilloids display capsaicin‐like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Although the cloned rat vanilloid receptor VR1 appears to account for both receptor binding and calcium uptake, the identification of vanilloids selective for one or the other response is of importance because these ligands may induce distinct patterns of biological activities.
Phorbol 12,13‐didecanoate 20‐homovanillate (PDDHV) evoked 45Ca2+‐uptake by rat dorsal root ganglion neurons (expressing native vanilloid receptors) in culture with an EC50 of 70 nM but inhibited [3H]‐resiniferatoxin (RTX) binding to rat dorsal root ganglion membranes with a much lower potency (Ki>10,000 nM). This difference in potencies represents a more than 100 fold selectivity for capsaicin‐type pharmacology.
45Ca2+ influx by PDDHV was fully inhibited by the competitive vanilloid receptor antagonist capsazepine, consistent with the calcium uptake occurring via vanilloid receptors.
PDDHV induced calcium mobilization in CHO cells transfected with the cloned rat vanilloid receptor VR1 with an EC50 of 125 nM and inhibited [3H]‐RTX binding to these cells with an estimated Ki of 10,000 nM. By contrast, PDDHV failed to evoke a measurable calcium response in non‐transfected CHO cells, confirming its action through VR1.
We conclude that PDDHV is two orders of magnitude more potent for inducing calcium uptake than for inhibiting RTX binding at vanilloid receptors, making this novel vanilloid a ligand selective for capsaicin‐type pharmacology. These results emphasize the importance of monitoring multiple endpoints for evaluation of vanilloid receptor structure‐activity relations. Furthermore, PDDHV now provides a tool to explore the biological correlates of capsaicin‐type vanilloid pharmacology.
British Journal of Pharmacology (1999) 128, 428–434; doi:10.1038/sj.bjp.0702810</description><subject>[3H]‐resiniferatoxin binding</subject><subject>Animals</subject><subject>Calcium - metabolism</subject><subject>capsaicin</subject><subject>Capsaicin - pharmacology</subject><subject>capsaicin‐type vanilloid pharmacology</subject><subject>Cell Membrane - metabolism</subject><subject>CHO Cells</subject><subject>Cloning, Molecular</subject><subject>Cricetinae</subject><subject>Diterpenes - pharmacology</subject><subject>DNA, Complementary - biosynthesis</subject><subject>DNA, Complementary - genetics</subject><subject>Female</subject><subject>Fluorescent Dyes</subject><subject>Ganglia, Spinal - cytology</subject><subject>Ganglia, Spinal - drug effects</subject><subject>native vanilloid receptors</subject><subject>Neurotoxins - pharmacology</subject><subject>phorboid vanilloids</subject><subject>Phorbol 12,13‐didecanoate 20‐homovanillate</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Drug - drug effects</subject><subject>Receptors, Drug - genetics</subject><subject>vanilloid receptor subtype 1 (VR1)</subject><subject>VR1‐transfected CHO cells</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFu1DAQhi0EokvhyhH5BbLMxPHGuSBBS1ukSkUr4Go5zoT1ktqRnS7NjUfgNXgtngS3W0GRkDjNSPN_3xx-xp4jLBGEepm2y3Y7LqGGUiE8YAus6lUhhcKHbAEAdYGo1AF7ktIWIB9r-ZgdIEiESlYL9mNNyXnXUzRTuHb-57fv0zwSHzchtsF1fGe8G4a8Jd65NA5m5taMyTh7Gx7cF-KJBrKT27lp5mbi3uSd_pA8kqVxCjHx4Hl-xI_Xp9zTVQw-ceO7G2jaELdD8NT9A-Sf1viUPerNkOjZ3TxkH0_efjg6K84vTt8dvT4vbCUlFBYU9mXTiKY0qrWlNbUQVnZSydIg9FI0pKDDVla9qvuuWUljVijrHmulhBSH7NXeO161l9RZ8lM0gx6juzRx1sE4_ffFu43-HHY6O3AlMQuWe4GNIaVI_W8WQd-UptNW59L0XWkZeHH_4734vqUcEPvAVzfQ_B-dfvP-TIgSxC90Mqsl</recordid><startdate>199909</startdate><enddate>199909</enddate><creator>Szallasi, A</creator><creator>Szabó, T</creator><creator>Bíró, T</creator><creator>Modarres, S</creator><creator>Blumberg, P M</creator><creator>Krause, J E</creator><creator>Cortright, D N</creator><creator>Appendino, G</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>199909</creationdate><title>Resiniferatoxin‐type phorboid vanilloids display capsaicin‐like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1</title><author>Szallasi, A ; Szabó, T ; Bíró, T ; Modarres, S ; Blumberg, P M ; Krause, J E ; Cortright, D N ; Appendino, G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4550-c081f299392a8bc2ca733c5d5852a10f539e80d1b54f87fd965aa6157f1788353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>[3H]‐resiniferatoxin binding</topic><topic>Animals</topic><topic>Calcium - metabolism</topic><topic>capsaicin</topic><topic>Capsaicin - pharmacology</topic><topic>capsaicin‐type vanilloid pharmacology</topic><topic>Cell Membrane - metabolism</topic><topic>CHO Cells</topic><topic>Cloning, Molecular</topic><topic>Cricetinae</topic><topic>Diterpenes - pharmacology</topic><topic>DNA, Complementary - biosynthesis</topic><topic>DNA, Complementary - genetics</topic><topic>Female</topic><topic>Fluorescent Dyes</topic><topic>Ganglia, Spinal - cytology</topic><topic>Ganglia, Spinal - drug effects</topic><topic>native vanilloid receptors</topic><topic>Neurotoxins - pharmacology</topic><topic>phorboid vanilloids</topic><topic>Phorbol 12,13‐didecanoate 20‐homovanillate</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Drug - drug effects</topic><topic>Receptors, Drug - genetics</topic><topic>vanilloid receptor subtype 1 (VR1)</topic><topic>VR1‐transfected CHO cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Szallasi, A</creatorcontrib><creatorcontrib>Szabó, T</creatorcontrib><creatorcontrib>Bíró, T</creatorcontrib><creatorcontrib>Modarres, S</creatorcontrib><creatorcontrib>Blumberg, P M</creatorcontrib><creatorcontrib>Krause, J E</creatorcontrib><creatorcontrib>Cortright, D N</creatorcontrib><creatorcontrib>Appendino, G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Szallasi, A</au><au>Szabó, T</au><au>Bíró, T</au><au>Modarres, S</au><au>Blumberg, P M</au><au>Krause, J E</au><au>Cortright, D N</au><au>Appendino, G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Resiniferatoxin‐type phorboid vanilloids display capsaicin‐like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>1999-09</date><risdate>1999</risdate><volume>128</volume><issue>2</issue><spage>428</spage><epage>434</epage><pages>428-434</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract>Although the cloned rat vanilloid receptor VR1 appears to account for both receptor binding and calcium uptake, the identification of vanilloids selective for one or the other response is of importance because these ligands may induce distinct patterns of biological activities.
Phorbol 12,13‐didecanoate 20‐homovanillate (PDDHV) evoked 45Ca2+‐uptake by rat dorsal root ganglion neurons (expressing native vanilloid receptors) in culture with an EC50 of 70 nM but inhibited [3H]‐resiniferatoxin (RTX) binding to rat dorsal root ganglion membranes with a much lower potency (Ki>10,000 nM). This difference in potencies represents a more than 100 fold selectivity for capsaicin‐type pharmacology.
45Ca2+ influx by PDDHV was fully inhibited by the competitive vanilloid receptor antagonist capsazepine, consistent with the calcium uptake occurring via vanilloid receptors.
PDDHV induced calcium mobilization in CHO cells transfected with the cloned rat vanilloid receptor VR1 with an EC50 of 125 nM and inhibited [3H]‐RTX binding to these cells with an estimated Ki of 10,000 nM. By contrast, PDDHV failed to evoke a measurable calcium response in non‐transfected CHO cells, confirming its action through VR1.
We conclude that PDDHV is two orders of magnitude more potent for inducing calcium uptake than for inhibiting RTX binding at vanilloid receptors, making this novel vanilloid a ligand selective for capsaicin‐type pharmacology. These results emphasize the importance of monitoring multiple endpoints for evaluation of vanilloid receptor structure‐activity relations. Furthermore, PDDHV now provides a tool to explore the biological correlates of capsaicin‐type vanilloid pharmacology.
British Journal of Pharmacology (1999) 128, 428–434; doi:10.1038/sj.bjp.0702810</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>10510454</pmid><doi>10.1038/sj.bjp.0702810</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | [3H]‐resiniferatoxin binding Animals Calcium - metabolism capsaicin Capsaicin - pharmacology capsaicin‐type vanilloid pharmacology Cell Membrane - metabolism CHO Cells Cloning, Molecular Cricetinae Diterpenes - pharmacology DNA, Complementary - biosynthesis DNA, Complementary - genetics Female Fluorescent Dyes Ganglia, Spinal - cytology Ganglia, Spinal - drug effects native vanilloid receptors Neurotoxins - pharmacology phorboid vanilloids Phorbol 12,13‐didecanoate 20‐homovanillate Rats Rats, Sprague-Dawley Receptors, Drug - drug effects Receptors, Drug - genetics vanilloid receptor subtype 1 (VR1) VR1‐transfected CHO cells |
| title | Resiniferatoxin‐type phorboid vanilloids display capsaicin‐like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1 |
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