Journal
EMBO JOURNAL
Volume 24, Issue 18, Pages 3224-3234Publisher
WILEY
DOI: 10.1038/sj.emboj.7600795
Keywords
substituted cysteine-accessibility method; transepithelial Ca2+ transport; transient receptor potential
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Funding
- NIDDK NIH HHS [R01 DK054368, DK-59530, DK-54368, R01 DK059530, P01 DK020543, DK-20543] Funding Source: Medline
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The transient receptor potential channel TRPV5 constitutes the apical entry pathway for transepithelial Ca2+ transport. We showed that TRPV5 was inhibited by both physiological intra- and extracellular acid pH. Inhibition of TRPV5 by internal protons was enhanced by extracellular acidification. Similarly, inhibition by external protons was enhanced by intracellular acidification. Mutation of either an extra- or an intracellular pH sensor blunted the crossinhibition by internal and external protons. Both internal and external protons regulated the selectivity filter gate. Using the substituted cysteine accessibility method, we found that intracellular acidification of TRPV5 caused a conformational change of the pore helix consistent with clockwise rotation along its long axis. Thus, rotation of pore helix caused by internal protons facilitates closing of TRPV5 by external protons. This regulation by protons likely contributes to pathogenesis of disturbances of Ca2+ transport in many diseased states. Rotation of pore helix may be a common mechanism for crossregulation of ion channels by extra- and intracellular signals.
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