PIP(2) Activates TRPV5 and Releases Its Inhibition by Intracellular Mg(2+)

The transient receptor potential type V5 channel (TRPV5) is a Ca(2+)-selective TRP channel important for epithelial Ca(2+) transport. Intracellular Mg(2+) causes a fast voltage-dependent block of the TRPV5 channel by binding to the selectivity filter. Here, we report that intracellular Mg(2+) binding to the selectivity filter of TRPV5 also causes a slower reversible conformational change leading to channel closure. We further report that PIP(2) activates TRPV5. Activation of TRPV5 by PIP(2) is independent of Mg(2+). Yet, PIP(2) decreases sensitivity of the channel to the Mg(2+)-induced slow inhibition. Mutation of aspartate-542, a critical Mg(2+)-binding site in the selectivity filter, abolishes Mg(2+)-induced slow inhibition. PIP(2) has no effects on Mg(2+)-induced voltage-dependent block. Thus, PIP(2) prevents the Mg(2+)-induced conformational change without affecting Mg(2+) binding to the selectivity filter. Hydrolysis of PIP(2) via receptor activation of phospholipase C sensitizes TRPV5 to the Mg(2+)-induced slow inhibition. These results provide a novel mechanism for regulation of TRP channels by phospholipase C–activating hormones via alteration of the sensitivity to intracellular Mg(2+).