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Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] is an important cofactor for ion channels. Affinity for this lipid is a major determinant of channel inhibition by depletion of PI(4,5)P 2  upon phospholipase C (PLC) activation. Little is known about what determines PI(4,5)P 2  affinity in mammalian ion channels. Here we report that two members of the Transient Receptor Potential Vanilloid (TRPV) ion channel family, TRPV5 and TRPV6 lack a positively charged residue in the TM4-TM5 loop that was shown to interact with PI(4,5)P 2  in TRPV1, which shows high affinity for this lipid. When this positively charged residue was introduced to either TRPV6 or TRPV5, they displayed markedly higher affinities for PI(4,5)P 2 , and were largely resistant to inhibition by PI(4,5)P 2  depletion. Furthermore, Ca 2+ -induced inactivation of TRPV6 was essentially eliminated in the G488R mutant, showing the importance of PLC-mediated PI(4,5)P 2  depletion in this process. Computational modeling shows that the introduced positive charge interacts with PI(4,5)P 2  in TRPV6.

A molecular determinant of phosphoinositide affinity in mammalian TRPV channels