*, Michael J. CATERINA, Tobias A. ROSEN, David JULIUS Capsaicin, the main pungent ingredient in 'hot' chili peppers, elicits burning pain by activating specific vanilloid receptors on sensory nerve endings. We have isolated a functional cdna encoding a capsaicin receptor from sensory neurons using an expression cloning strategy. The cloned vanilloid receptor VR1 is a nonselective cation channel with six transmembrane domains that is structurally related to a member of the TRP family. VR1 is also activated by increases in temperature in the nonoxious range 43. We also find that protons decrease the temperature threshold for VR1 activation such that even moderately acidic conditions ph 5.9 activate VR1 at room temperature. Analysis of single-channel currents in excised membrane patches suggests that heat or proton gates VR1 directly. VR1 can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit pain. capsaicin / receptor / ion channel / heat / proton / pain C- fiber. nociceptor,, 1, 2. nociceptor,,. nociceptor,,,.,. resiniferatoxin capsazepine, 3, 4.,. 6,,, 5, 7.., nociceptor, Ca 2., Ca 2, 5. vanillyl, resiniferatoxin vanilloid 1a, vanilloid receptor subtype 1 VR1 The Capsaicin Receptor A Heat- and Proton-activated Ion Channel Makoto TOMINAGA*, Michael J. CATERINA, Tobias A. ROSEN, David JULIUS Department of Cellular and Molecular Pharmacology, University of California, San Francisco, U.S.A. *
a CH 3 CH CH CH O C NH CH 2 CH 3 CH 2 4 OCH 3 OH a b 2 na 40 s A A A C N 1 ab a vanillyl, resiniferatoxin vanilloid. b 6, 5, 6 H5., 3 ankyrin repeat domain A,. 5. VR1 Northern blot,., in situ hybridization, VR1., VR1 nociception. VR1, 6 1b. 6,, TRP family. VR1. 2, resiniferatoxin,, capsazepine, ruthenium red., VR1,, VR1 Ca 2. Ca 2 P Ca /P Na 9.6, Ca 2.,, bath solution, inside-out, outside-out, Na 77 ps ph 5.4 b c 2 100 nm 44 ph 5.4 capasazepine 1 na 20 s a 1 µm 46a,, bph 5.4,, Ca 2 free, 60 mv. capsazepine 10 µm. Ca 2,. c 100 nm, 44, ph 5.4, excised patch, 40 mv. 2c. excised patch,.,,,.,,.,
,.,,., VR1, Ca 2,., Ca 2,, Ca 2,, Ca 2 2a 5. PI., trp transient receptor potential,.,, Ca 2, trp Ca 2, Montelltrp 6., TRP Ca 2 store, Ca 2 store-operated Ca 2 channel. VR1 TRP family, Ca 2, VR1, TRP., VR1 store-operated Ca 2 channel,. VR1, Ca 2 thapsigargin Ca 2., storeoperated Ca 2 channel SKF 96365,., VR1 store-operated Ca 2 channel, 5. VR1,. TRP, Ca 2 store,,,,, VR1. burning pain., 1 a 1.2 1.0 0.8 ph 6.4 0.6 ph 7.4 0.4 0.2 0 9 8 7 6 5 log M b 300 250 200 ph 6.4 150 ph 7.4 100 50 0 20 25 30 35 40 45 50 pa/pf c 1 0.8 0.6 0.4 0.2 0 8 7 6 5 4 3 ph 3 a. ph 7.4 EC50 111 nm. ph 6.4 EC50 60 nm. b. ph 7.4 43. ph 6.4, 37. c. EC 50pH 5.4. 7, VR1., 43, 49 3b. VR1., 43
., VR1, Ca 2,,,, VR1.,, 2c., Ca 2,, 2a 7.,, 8, 9, VR1.,, Ca 2, VR1 heat sensor.,. heat sensor, Tsr,.,, 10., ph 6.,, 11., VR1 ph 7.4 6.4,, submaximal 3a, b. ph 6.4,,, EC 50 1.9 3a. ph 6.4, 3b.,,. VR1. ph 6.4, 37,.,,, VR1, 22 VR1., ph 2b. ph 6.0, EC 50pH 5.4, 3c. H., Ca,,,,, 2b, c 7.,, 2. 1 Na 12, 13, 1, 11, 14. degenerin family 2 DRASIC dorsal root ganglia acid sensing ion channel 15,. DRASIC, DRASIC, VR1. VR1 3.,,.,.,,.,.,., VR1 2. VR1 TRP family VR1,, VR1,. aconitine veratridine, Na., 16., VR1.,.
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