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The Journal of Neuroscience, January 15, 1999, 19(2):529-538
Capsaicin Binds to the Intracellular Domain of the Capsaicin-Activated Ion Channel
Jooyoung Jung1, Sun Wook Hwang1, Jiyeon Kwak1, Soon-Youl Lee1, Chang-Joong Kang1, Won Bae Kim2, Donghee Kim3, and Uhtaek Oh1 1 The Sensory Research Group, Creative Research Initiatives, Seoul National University, College of Pharmacy, Kwanak, Seoul 151-742, Korea, 2 Research Laboratories of Dong-A Pharmaceuticals, Yongin, Krunggi 449-900, Korea, and 3 Department of Physiology and Biophysics, Finch University of Health Sciences, The Chicago Medical School, North Chicago, Illinois 60064-3095
Capsaicin (CAP) excites small sensory neurons, causing pain, neurogenic inflammation, and other visceral reflexes. These effects have been proposed to be the result of CAP activation of a nonselective cation current. It is generally assumed that CAP binds to an extracellular domain of the membrane receptor. However, the exact binding site is not known because of the lipophilic nature of CAP. To determine whether the binding domain is extracellular or intracellular, we tested the effect of a synthetic water-soluble CAP analog, DA-5018·HCl, on current activation. CAP activated the 45 pS (at
60 mV) nonselective cation channel from either side of the membrane. However, DA-5018·HCl, which had a greater potency and efficacy than CAP, activated the channels only from the cytosolic side of the patch membrane in a capsazepine, a CAP receptor antagonist, reversible manner. When applied extracellularly, DA-5018·HCl did not, but CAP did, activate whole-cell currents in sensory neurons, as well as in oocytes expressing vanilloid receptor 1, a recently cloned CAP receptor. Hydrogen ions, reported as a possible endogenous activator of cation current, failed to elicit any current when acidic medium (pH 5.0-6.0) was applied intracellularly, indicating that H+ does not mediate the CAP effect. These results indicate that CAP and its analog bind to the cytosolic domain of the CAP receptor and suggest that an endogenous CAP-like substance other than H+ may be present in the cell.
Key words: capsaicin receptor; VR1; binding domain; DA-5018; capsazepine; acid; pain
Copyright © 1999 Society for Neuroscience 0270-6474/99/192529-10$05.00/0
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