Hydrolysis of Phosphatidylinositol 4,5-bisphosphate Mediates Calcium-induced Inactivation of TRPV6 Channels
Overview
Affiliations
TRPV6 is a member of the transient receptor potential superfamily of ion channels that facilitates Ca(2+) absorption in the intestines. These channels display high selectivity for Ca(2+), but in the absence of divalent cations they also conduct monovalent ions. TRPV6 channels have been shown to be inactivated by increased cytoplasmic Ca(2+) concentrations. Here we studied the mechanism of this Ca(2+)-induced inactivation. Monovalent currents through TRPV6 substantially decreased after a 40-s application of Ca(2+), but not Ba(2+). We also show that Ca(2+), but not Ba(2+), influx via TRPV6 induces depletion of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2) or PIP(2)) and the formation of inositol 1,4,5-trisphosphate. Dialysis of DiC(8) PI(4,5)P(2) through the patch pipette inhibited Ca(2+)-dependent inactivation of TRPV6 currents in whole-cell patch clamp experiments. PI(4,5)P(2) also activated TRPV6 currents in excised patches. PI(4)P, the precursor of PI(4,5)P(2), neither activated TRPV6 in excised patches nor had any effect on Ca(2+)-induced inactivation in whole-cell experiments. Conversion of PI(4,5)P(2) to PI(4)P by a rapamycin-inducible PI(4,5)P(2) 5-phosphatase inhibited TRPV6 currents in whole-cell experiments. Inhibiting phosphatidylinositol 4 kinases with wortmannin decreased TRPV6 currents and Ca(2+) entry into TRPV6-expressing cells. We propose that Ca(2+) influx through TRPV6 activates phospholipase C and the resulting depletion of PI(4,5)P(2) contributes to the inactivation of TRPV6.
Baskaran P, Gustafson N, Chavez N Pharmaceuticals (Basel). 2024; 17(8).
PMID: 39204203 PMC: 11359803. DOI: 10.3390/ph17081098.
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Humer C, Radiskovic T, Horvati K, Lindinger S, Groschner K, Romanin C Int J Mol Sci. 2024; 25(1).
PMID: 38203789 PMC: 10779433. DOI: 10.3390/ijms25010618.
Molecular pharmacology of the onco-TRP channel TRPV6.
Neuberger A, Sobolevsky A Channels (Austin). 2023; 17(1):2266669.
PMID: 37838981 PMC: 10578198. DOI: 10.1080/19336950.2023.2266669.
Structural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A.
Lee B, De Jesus Perez J, Moiseenkova-Bell V, Rohacs T Nat Commun. 2023; 14(1):5883.
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Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging.
Yuan Z, Hansen S Membranes (Basel). 2023; 13(2).
PMID: 36837753 PMC: 9966874. DOI: 10.3390/membranes13020250.