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Comparative Study
. 2000 May 23;97(11):6155-60.
doi: 10.1073/pnas.97.11.6155.

Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances

S W Hwang  1 , H Cho, J Kwak, S Y Lee, C J Kang, J Jung, S Cho, K H Min, Y G Suh, D Kim, U Oh
Affiliations
Comparative Study

Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances

S W Hwang et al. Proc Natl Acad Sci U S A. .

Abstract

Capsaicin, a pungent ingredient of hot peppers, causes excitation of small sensory neurons, and thereby produces severe pain. A nonselective cation channel activated by capsaicin has been identified in sensory neurons and a cDNA encoding the channel has been cloned recently. However, an endogenous activator of the receptor has not yet been found. In this study, we show that several products of lipoxygenases directly activate the capsaicin-activated channel in isolated membrane patches of sensory neurons. Among them, 12- and 15-(S)-hydroperoxyeicosatetraenoic acids, 5- and 15-(S)-hydroxyeicosatetraenoic acids, and leukotriene B(4) possessed the highest potency. The eicosanoids also activated the cloned capsaicin receptor (VR1) expressed in HEK cells. Prostaglandins and unsaturated fatty acids failed to activate the channel. These results suggest a novel signaling mechanism underlying the pain sensory transduction.

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Figures

Figure 1
Figure 1
Direct activation of icap by 12-(S)-HPETE, one of LO products. (A) 12-(S)-HPETE in 10 μM activates single-channel currents in an inside-out membrane patch of a cultured dorsal root ganglion neuron containing capsaicin (CAP)-activated channels. (Inset) Current traces in an expanded time scale. (B) Block by 10 μM capsazepine (CZP) of single channel currents activated by 2 μM 12-(S)-HPETE. (Insets) A summary of the block by capsazepine (Left). Channel current is expressed in channel activity (NPo). **, P < 0.01. (Right) Current-voltage relationship of channels activated by capsaicin (open circle, n = 11) and 12-(S)-HPETE (filled triangle, n = 5–8). The two I–V curves are superimposable. Concentrations are expressed in micromolar.
Figure 2
Figure 2
Activation of VR1 by products of LOs in an inside-out membrane patch of a VR1-transfected HEK 293 cell. (Inset) Current traces in an expanded time scale (Left) and current-voltage relationship of channels (Right) activated by 12-(S)-HPETE in HEK 293 cells transfected with VR1. 15-(S)-HETE and 15-(S)-HPETE are also capable of activating VR1 expressed in HEK 293 cells (lower traces).
Figure 3
Figure 3
Various LO products (A) and anandamide (B) in activating icap in inside-out patches of cultured dorsal root ganglion neurons. (C) A summary of effects of various LO products on activating icap. Relative channel activities of each 10 μM LO product are normalized to the channel activity (NPo) obtained with 10 μM 12-(S)-HPETE. DiHETE, 8-(R)-15-(S)-dihydroxyeicosatetraenoic acid; Hepox. A3 or B3, hepoxilin A3 or B3. Numbers above the bars represent the number of experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.001 compared with NPo of 12-(S)-HPETE.
Figure 4
Figure 4
(A) An example trace showing a dose-response relationship of 12-(S)-HPETE in activating icap. (B) Channel activity (NPo) obtained after application of 12-(S)-HPETE (n = 13), 15-(S)-HPETE (n = 9), 5-(S)-HETE (n = 11), LTB4 (n = 9), and anandamide (n = 8) in different concentrations is plotted against concentrations of the lipids. Each data point is fitted to the Hill equation: NPo = maximal NPo × [1/{1 + (Kd/[lipid])n}].
Figure 5
Figure 5
Effects of various lipids other than products of LOs on icap in cultured dorsal root ganglion neurons. (A) PGE2 fails to activate icap in inside-out membrane patch. (B) Current response of icap to AA. (C) Block by baicalein, a 12-LO inhibitor, of the icap activated by AA. (D) Relative channel activities of the various lipids expressed as normalized to the channel activity (NPo) obtained with 10 μM 12-(S)-HPETE. DHA, docosahexaenoic acid; DHL, dihomo-γ-linolenic acid; SAG, 1-stearyl-2-arachidonyl-sn-glycerol. Numbers above the bars represent the number of experiments. Relative channel activities of the lipids are significantly (P < 0.001) different from the channel activity (NPo) of 10 μM 12-(S)-HPETE.
Figure 6
Figure 6
(A) Chemical structures of capsaicin and 12-(S)-HPETE. Capsaicin is divided into three functional regions as described by others (30). (B) Molecular modeling overlay of minimum-energy conformations of capsaicin (green) and 12-(S)-HPETE (yellow). Oxygen and nitrogen atoms are colored in red and blue, respectively.
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