Fig. 7. Summary of ligand binding and ligand-dependent gating of TRPM8 channels.

(A) The binding sites for PIP₂ (1), type I agonists (2), type II agonists (3), Ca²⁺ ions (4), competitive antagonists (5), and noncompetitive agonists (6) are located surrounding the S4b in TRPM8. Representative ligands, PIP₂ (red), C3 (yellow), AITC (teal), TC-I (lime), and Ca²⁺ (green), are shown in surface or sphere and highlighted by dashed lines. (B) Conformational changes of S4b, S5, and the S4-S5 linker in the closed C₀ (silver-gray), closed C₁ (yellow), O (blue), and D (brown) states. Secondary structures and S4-S5 linker motions indicated by lines and arrows. PIP₂, C3, AITC, and TC-I shown as sticks and Ca²⁺ ions as spheres. Neighboring protomers colored in white. (C) Structural diagram illustrating the conformational change from the O state to the D state and the D state–dependent inhibition by antagonists. Ligands and S6 gate residue Val⁹⁷⁶ shown as sticks and Ca²⁺ as green spheres. Insets show antagonist binding highlighted in yellow shades and red arrows.