2007 Fiscal Year Final Research Report Summary
Molecular identification and functional analysis of a caffeine receptor on the plasma membrane.
| Project/Area Number |
18390067
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General physiology
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| Research Institution | National Institute for Physiological Sciences |
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Principal Investigator |
KUBO Yoshihiro National Institute for Physiological Sciences, Department of Molecular Physiology, Professor (80211887)
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| Co-Investigator(Kenkyū-buntansha) |
SAITOH Osamu Nagahama Institute of Bio-Science and Technology, Department of Bio-Science, Professor (60241262)
TATEYAMA Michihiro National Institute for Physiological Sciences, Department of Molecular Physiology, Associate Professor (30276472)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Physiology / Neuroscience / Biomolecule / Protein / Signal transduction |
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| Research Abstract |
Caffeine has various well-characterized pharmacological effects mediated e.g. via ryanodine receptor stimulation and phosphodiesterase inhibition. However, it was recently reported that application of caffeine to STC-1 mouse gastrointestinal endocrine cells induces a rapid increase in intracellular Ca^<2+> (Ca^<2+>; ) that is suppressed by inhibition of phospholipase C. This suggests a novel pharmacological action for caffeine. We observed that caffeine-induced increases in Ca^<2+>i in fura-2-loaded STC-1 cells were dependent on extracellular Ca^<2+> and were suppressed by TRP (Transient Receptor Potential) channel blockers. In addition, Ca^<2+>i imaging and electrophysiological analyses showed that mouse TRPA1 channels were activated by mM concentrations of caffeine in heterologous expression systems such as HEK293T cells and Xenopus oocytes. These responses to caffeine were confirmed in acutely dissociated dorsal root ganglion sensory neurons from wild-type (WT) mice, which are known to express TRPA1, but were not seen in neurons from TRPA1 knock-out (KO) mice. Expression of TRPA1 protein 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 in two-bottle preference tests. Finally, we observed that the activity of human TRPA1 channels is suppressed by caffeine, in clear contrast to the mouse channels. Our findings demonstrated caffeine activates a Ca^<2+>-permeable TRPA1 channel in mouse but suppresses the activity of the human orthologue. We also showed that mouse TRPA1 channels expressed in sensory neurons cause an aversion to drinking caffeine-containing water, suggesting they mediate the perception of caffeine.
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