Background:The gating mechanism of transient receptor potential melastatin 8 (TRPM8) channels remains elusive. Results: Mutations neighboring the C-end region of the TRPM8 channel inner gate modulate allosteric coupling. Conclusion:The region adjacent to the inner gate in TRPM8 channels is pivotal for allosteric channel activation. Significance: These findings increase our understanding of the allosteric mechanism of TRPM8 channel gating.

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