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<p>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.</p>

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Symmetry-driven gating of TRPM8 by PIP2 and menthol

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Sun-Hong Kim,
  • Chansik Hong,
  • Hyunwoo Park,
  • Youngchang Ju,
  • Youngsoo Hwang,
  • Jinhyeong Kim,
  • Sangho Ji,
  • Wookyung Yu,
  • Insuk So,
  • Hyung Ho Lee

摘要

TRPM8, a cold-activated ion channel, enables mammals to sense cooling agents such as menthol. While PIP2 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 PIP2-induced two-fold symmetric intermediate and an icilin-bound open state. Our results reveal that PIP2 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 PIP2-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 PIP2 and cooling agonists gate the channel.