Analogous cation–π bonds and the girdle are seen in many closed TRP channel structures. Our data indicate that the Y602–R616 cation–π interactions link the four S4–S5 linker helices together, forming a girdle backing the closed gate. Our experiments with TRPV4 mutants indicate that the resting-closed state remains stable while the bond is substituted by a salt bridge or disulfide bond, whereas disruption of the contact by mutations like Y602C or R616Q produces gain-of-function phenotypes when TRPV4 is heterologously expressed in the Xenopus oocyte or yeast.

A cation–π bond between the conservative residues Y602 and R616 of neighboring subunits appears likely in many homologous channel structures in a closed state. Among the >60 known TRP vanilloid subfamily (V) 4 mutations that interfere with bone development are Y602C or R616Q at the S4–S5 linker.

Inappropriate gating can lead to pathologies. Polymodal transient receptor potential (TRP) channels have been shown to integrate mechanical, chemical, electric, and thermal stimuli. In many cases, it can be achieved even at the level of a single receptor molecule. An adequate response of a living cell to the ever-changing environment requires integration of numerous sensory inputs.

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