Introduction
The transient receptor potential vanilloid 1 (TRPV1) ion channel is a heat- and ligand-activated cation channel widely recognized for its central role in pain detection and inflammatory hypersensitivity. It responds to noxious temperatures, capsaicin, protons, and endogenous inflammatory mediators, making it a crucial molecular sensor in the peripheral nervous system. TRPV1 is a high-value therapeutic target for analgesic drug development, and therefore, understanding its three-dimensional architecture is essential for elucidating its gating mechanism and ligand recognition.
Structural Highlights
Recent high-resolution cryo-electron microscopy studies have revealed the detailed structure of human TRPV1 in multiple functional states, including the apo (inactive), capsaicin-bound, and toxin-bound conformations. TRPV1 forms a homotetramer, with each subunit contributing six transmembrane helices (S1–S6), a pore-forming loop, and large cytoplasmic ankyrin-repeat domains.
The vanilloid-binding pocket, located between the S3–S4 helices and the S4–S5 linker, was clearly visualized, revealing how capsaicin stabilizes rearrangements in the S4–S5 linker that propagate toward the S6 helices to open the pore. Toxin-bound structures exhibit an even wider pore diameter, representing a fully activated gating state. Comparison across these structural states highlights the sequence of conformational transitions that underlie heat and ligand-activated gating.
Significance
These cryo-EM structures provide a mechanistic framework for understanding how TRPV1 integrates chemical and thermal stimuli to control ion permeation. The detailed visualization of ligand-binding pockets and pore conformations enables structure-based development of novel analgesic compounds targeted toward inflammatory and neuropathic pain. Furthermore, these structures offer insights into how lipid environment, toxins, and small molecules differentially modulate TRPV1 activity, establishing a foundation for rational drug design.
References
