Abstract
Uncaria rhynchophylla (UR), an herb traditionally used in Eastern medicine, is recognized for its therapeutic applications in treating hypertension and inflammation. However, the specific molecular mechanisms how UR and its bioactive constituents modulate inflammatory pathways remain unknown. Here, we discovered that UR extract activated TRPV1 in HEK293T cell. Notably, consecutive application of UR extract on TRPV1 exhibited inhibitory action through channel desensitization. Further analysis led to the isolation of hirsuteine, a compound within UR extract that robustly activates and subsequently desensitizes TRPV1 in HEK293T cells. The molecular docking simulation revealed that the residues S501, F507, Y511, L515, and E570 in TRPV1 were associated with the binding of HST. Additionally, applying HST on TRPV1-positive sensory neurons showed significantly reduced electrical activity compared to capsaicin. Our findings collectively suggest that UR and HST possess distinct agonistic and desensitizing effects on TRPV1.