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The transient receptor potential channel TRPV5 contributes to the apical entry pathway for transcellular calcium reabsorption
in the kidney. Acid load causes hypercalciuria in animals and humans. We have previously reported that intracellular protons
directly inhibit TRPV5. Here, we examined the effects of intracellular pH on single-channel activity of TRPV5. We found that
TRPV5 channels exhibit full and subconductance open states in excised inside–out patches of Chinese hamster ovary cells. The
slope conductance values (Na+ as a charge carrier, between −25 and −75 mV) for full and subconductance opening at intracellular pH 7.4 were 59 ± 6 and 29 ± 3 pS, respectively. Intracellular acidification
caused a small decrease in single-channel conductance. Importantly, intracellular acidification decreased open probability
for the full and subconductance states and increased probability for closing. To investigate how intracellular protons decrease
open probability of the channel, we proposed a simple three-state model for open–subconductance–closed state transition and
examined the effects of acidification on the respective forward and reverse rate constants. We found that intracellular acidification
decreases opening of TRPV5 predominantly by promoting a transition from the subconductance to the closed state. Thus, intracellular
acidification directly inhibits TRPV5 by causing a conformational change(s) leading to a decrease of open probability of TRPV5
as well as of the single-channel conductance.
Seung-Kuy Cha and Wasey Jabbar contributed equally to this work. 相似文献
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