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Vol. 56, Issue 3, 581-587, September 1999
National Cancer Institute, Bethesda, Maryland (A.S., P.M.B.); and
Neurogen Corp., Branford, Connecticut (L.L.A., J.E.K., D.N.C.)
[3H]Resiniferatoxin (RTX) binding and calcium uptake by
rat dorsal root ganglion (DRG) neurons show distinct structure-activity relations, suggestive of independent vanilloid receptor (VR) subtypes. We have now characterized ligand binding to rat VR1 expressed in human
embryonic kidney (HEK293) and Chinese hamster ovary (CHO) cells and
compared the structure-activity relations with those for calcium
mobilization. Human embryonic kidney cells (HEK293/VR1 cells) and
Chinese hamster ovary cells transfected with VR1 (CHO/VR1 cells) bound
[3H]RTX with affinities of 84 and 103 pM, respectively,
and positive cooperativity (Hill numbers were 2.1 and 1.8). These
parameters are similar to those determined with rat DRG membranes
expressing native VRs (a Kd of 70 pM and a
Hill number of 1.7). The typical vanilloid agonists olvanil and
capsaicin inhibited [3H]RTX binding to HEK293/VR1 cells
with Ki values of 0.4 and 4.0 µM,
respectively. The corresponding values in DRG membranes were 0.3 and
2.5 µM. HEK293/VR1 cells and DRG membranes also recognized the novel
vanilloids isovelleral and scutigeral with similar
Ki values (18 and 20 µM in HEK293/VR1
cells; 24 and 21 µM in DRGs). The competitive vanilloid receptor
antagonist capsazepine inhibited [3H]RTX binding to
HEK293/VR1 cells with a Ki value of 6.2 µM
and binding to DRG membranes with a Ki value
of 8.6 µM. RTX and capsaicin induced calcium mobilization in
HEK293/VR1 cells with EC50 values of 4.1 and 82 nM,
respectively. Thus, the relative potencies of RTX (more potent for
binding) and capsaicin (more potent for calcium mobilization) are
similar in DRG neurons and cells transfected with VR1. We conclude that
VR1 can account for both the ligand binding and calcium uptake observed
in rat DRG neurons.
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