Fig. 6: Ca²⁺-dependent, CBTA-dependent and TPPO-dependent regulation of TRPM5 gating.

Cartoon illustrating how Ca²⁺, CBTA and TPPO differentially modulate TRPM5 activation. Canonical activation requires Ca²⁺ binding at the agonist site Ca_TMD and the modulatory site Ca_ICD. CBTA, a noncalcium agonist, binds the upper vestibule of the S1–S4 pocket directly above Ca_TMD and mimics the dual roles of Ca_TMD and Ca_ICD, merging agonist activation with voltage modulation. CBTA also renders TRPM5 supersensitive to Ca²⁺, synergistically hyperactivating the channel even at near-resting Ca²⁺ levels. In contrast, the inhibitor TPPO binds the same pocket but stabilizes a nonconductive conformation.