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Proc Natl Acad Sci U S A
2008 Nov 11;10545:17373-8. doi: 10.1073/pnas.0809769105.
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Caffeine activates mouse TRPA1 channels but suppresses human TRPA1 channels.
Nagatomo K
,
Kubo Y
.
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Caffeine has various well-characterized pharmacological effects, but in mammals there are no known plasma membrane receptors or ion channels activated by caffeine. We observed that caffeine activates mouse transient receptor potential A1 (TRPA1) in heterologous expression systems by Ca(2+)(i) imaging and electrophysiological analyses. These responses to caffeine were confirmed in acutely dissociated dorsal root ganglion sensory neurons from WT mice, which are known to express TRPA1, but were not seen in neurons from TRPA1 KO mice. Expression of TRPA1 was detected immunohistochemically in nerve fibers and bundles in the mouse tongue. Moreover, WT mice, but not KO mice, showed a remarkable aversion to caffeine-containing water. These results demonstrate that mouse TRPA1 channels expressed in sensory neurons cause an aversion to drinking caffeine-containing water, suggesting they mediate the perception of caffeine. Finally, we observed that caffeine does not activate human TRPA1; instead, it suppresses its activity.
Fig.2. Caffeine-induced currents in Xenopus oocytes expressing mTRPA1. (A) Current recordings were obtained under 2-electrode voltage clamp by applying step pulses to +60 mV from a holding potential of −20 mV repeatedly every 2 s, before and after application of agonists. Responses to 5 mM caffeine (Top), 100 μM AITC (Middle), and 400 μM menthol (Bottom) are shown. (B) Time course of the change in peak current amplitude after application of agonists. (C and D) Current–voltage relationship for responses to the indicated concentrations of caffeine. (C) During the steady state after 30-s exposure to the indicated concentrations of caffeine, 300-ms step pulses from −80 to +80 mV were applied and then stepped back to +60 mV for 100 ms every 1 s from the holding potential of −20 mV. (D) y axis shows the current amplitudes at the indicated membrane potentials in the presence of caffeine (0.1–10 mM). (Inset) An expanded view of the voltage range at which inward current was observed. The n values indicate numbers of recorded oocytes, and the plots depict mean ± SEM.
Fig.6. Current recordings from Xenopus oocytes expressing hTRPA1. Using a 2-electrode voltage clamp, 200-ms ramp pulses from −100 to +100 mV were applied every 5 s from a holding potential of −60 mV to oocytes expressing mTRPA1 (A and C) or hTRPA1 (B and D). Agonists were applied at the times indicated by the bars. (A and C) Responses of mTRPA1 to both caffeine and AITC were confirmed; C is an expanded view of the boxed region in A. (B and D) The response of hTRPA1 to AITC was confirmed, but a decrease in the current amplitude was observed upon application of caffeine. The suppression was more clearly observed when basal channel current was increased by application and washout of AITC (B; expanded in D) or in the presence of AITC (B). Recordings similar to A and B were obtained from 3 cells, and representative data are shown.
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