Resiniferatoxin-type phorboid vanilloids display capsaicin-like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1

A. Szallasi, T. Szabó, T. Bíró, S. Modarres, P. M. Blumberg, J. E. Krause, D. N. Cortright, G. Appendino

Research output: Contribution to journalArticle

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Abstract

1. 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. 2. 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 (K(i) > 10,000 nM). This difference in potencies represents a more than 100 fold selectivity for capsaicin-type pharmacology. 3. 45Ca2+ influx by PDDHV was fully inhibited by the competitive vanilloid receptor antagonist capsazepine, consistent with the calcium uptake occurring via vanilloid receptors. 4. 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 K(i) of 10,000 nM. By contrast, PDDHV failed to evoke a measurable calcium response in non-transfected CHO cells, confirming its action through VR1. 5. 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.

Original languageEnglish
Pages (from-to)428-434
Number of pages7
JournalBritish Journal of Pharmacology
Volume128
Issue number2
DOIs
Publication statusPublished - 1999

Fingerprint

TRPV Cation Channels
Diagnosis-Related Groups
Capsaicin
Neurons
Calcium
CHO Cells
Spinal Ganglia
Pharmacology
Ligands
Calcium-Sensing Receptors
resiniferatoxin
phorbol 12,13-didecanoate 20-homovanillate
TRPV1 receptor
Membranes

Keywords

  • [H]-resiniferatoxin binding capsaicin
  • Capsaicin-type vanilloid pharmacology
  • Native vanilloid receptors
  • Phorboid vanilloids
  • Phorbol 12,13-didecanoate 20-homovanillate
  • Vanilloid receptor subtype 1 (VR1)
  • VR1-transfected CHO cells

ASJC Scopus subject areas

  • Pharmacology

Cite this

Resiniferatoxin-type phorboid vanilloids display capsaicin-like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1. / Szallasi, A.; Szabó, T.; Bíró, T.; Modarres, S.; Blumberg, P. M.; Krause, J. E.; Cortright, D. N.; Appendino, G.

In: British Journal of Pharmacology, Vol. 128, No. 2, 1999, p. 428-434.

Research output: Contribution to journalArticle

Szallasi, A. ; Szabó, T. ; Bíró, T. ; Modarres, S. ; Blumberg, P. M. ; Krause, J. E. ; Cortright, D. N. ; Appendino, G. / Resiniferatoxin-type phorboid vanilloids display capsaicin-like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1. In: British Journal of Pharmacology. 1999 ; Vol. 128, No. 2. pp. 428-434.
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AU - Bíró, T.

AU - Modarres, S.

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