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Transient receptor potential melastatin member 4 (TRPM4) and 5 (TRPM5) channels are Ca 2+ -activated nonselective cation channels. Intracellular Ca 2+ is the most important regulator for them to open, though PI(4,5)P 2 , a membrane phosphoinositide, has been reported to regulate their Ca 2+ -sensitivities. We previously reported that negatively-charged amino acid residues near and in the TRP domain are necessary for the normal Ca 2+ sensitivity of TRPM4. More recently, a cryo-electron microscopy structure of Ca 2+ -bound (but closed) TRPM4 was reported, proposing a Ca 2+ -binding site within an intracellular cavity formed by S2 and S3. Here, we examined the functional effects of mutations of the amino acid residues related to the proposed Ca 2+ -binding site on TRPM4 and also TRPM5 using mutagenesis and patch clamp techniques. The mutations of the amino acid residues of TRPM4 and TRPM5 reduced their Ca 2+ -sensitivities in a similar way. On the other hand, intracellular applications of PI(4,5)P 2 recovered Ca 2+ -sensitivity of desensitized TRPM4, but its effect on TRPM5 was negligible. From these results, the Ca 2+ -binding sites of TRPM4 and TRPM5 were shown to be formed by the same amino acid residues by functional analyses, but the impact of PI(4,5)P 2 on the regulation of TRPM5 seemed to be smaller than that on the regulation of TRPM4.

TRPM4 and TRPM5 Channels Share Crucial Amino Acid Residues for Ca2+ Sensitivity but Not Significance of PI(4,5)P2