ArticleProceedings of the National Academy of Sciences of the United States of America2026
Distinct functional open states of the polymodal nociceptor TRPV1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The polymodal nociceptor TRPV1 integrates diverse physical and chemical stimuli, yet whether these inputs drive a common activated state remains unresolved. Here, we show that TRPV1 activators stabilize functionally distinct open states that yield discrete single-channel conductance levels. These functional states appear to arise from distinct open-pore conformations, as evidenced by anomalous mole fraction effect measurements. Structurally, stimulus-specific changes in pore conformation were directly observed using site-directed fluorescence recordings, consistent with Rosetta-guided structural models. Notably, coactivation by two stimuli markedly slows channel opening rather than producing synergistic acceleration, suggesting potential conformational incompatibility across subunits. Together, these findings define TRPV1 gating as a stimulus-partitioned, multistate process and highlight opportunities for selective modulation of TRPV1 in pain management.
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