Symmetry-driven gating of TRPM8 by PIP<sub>2</sub> and menthol.
basic_science · Level V
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- Record sourced from PubMed, PMID 42481499.
- Also identified by DOI 10.1038/s41467-026-75793-0.
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Abstract
TRPM8, a cold-activated ion channel, enables mammals to sense cooling agents such as menthol. While PIP<sub>2</sub> is essential for menthol-induced activation of TRPM8, the precise cooperative mechanism and the specific binding mode of menthol have remained elusive. Here, we present cryo-EM structures of mouse TRPM8 in diverse conformations, including a PIP<sub>2</sub>-induced two-fold symmetric intermediate and an icilin-bound open state. Our results reveal that PIP<sub>2</sub> binding initiates a symmetry-breaking event, priming the channel for activation through a noncanonical intermediate states. The subsequent binding of cooling agonists promotes a transition back to four-fold symmetry. Notably, we find that menthol stabilizes the PIP<sub>2</sub>-bound state, thereby overcoming channel desensitization, while icilin, in concert with calcium, stabilizes a fully open conformation. Together, these structures illuminate a stepwise activation pathway involving distinct symmetry transitions and define the cooperative allosteric mechanism by which PIP<sub>2</sub> and cooling agonists gate the channel.