High‐resolution structures of transient receptor potential vanilloid channels: Unveiling a functionally diverse group of ion channels

Abstract

Transient receptor potential vanilloid (TRPV) channels are part of the superfamily of TRP ion channels and play important roles in widespread physiological processes including both neuronal and non-neuronal pathways. Various diseases such as skeletal abnormalities, chronic pain, and cancer are associated with dysfunction of a TRPV channel. In order to obtain full understanding of disease pathogenesis and create opportunities for therapeutic intervention, it is essential to unravel how these channels function at a molecular level. In the past decade, incredible progress has been made in biochemical sample preparation of large membrane proteins and structural biology techniques, including cryo-electron microscopy. This has resulted in high resolution structures of all TRPV channels, which has provided novel insights into the molecular mechanisms of channel gating and regulation that will be summarized in this review.

A cooperative knock-on mechanism underpins Ca2+-selective cation permeation in TRPV channels

“…1 ). In addition to this conserved transmembrane architecture, members of the TRP superfamily display highly diverse extramembrane loops and N- and C-terminal domains between the different subfamilies ( Van Goor et al, 2020 ).…”

TRPV4 integrates matrix mechanosensing with Ca2+ signaling to regulate extracellular matrix remodeling

“…A second clue may come from structural differences among individual channels. Recent electron microscopy data show significant differences in 3D structures among TRP subfamilies, and even among members of the same subfamily [91,92]. Further, certain motifs in the intracellular domains of TRP channels may contribute to variations in their regulation and function.…”

“…Overall, these examples illustrate the complexity of the structure‐function relationships of TRP channels. More in‐depth discussion of these relationships can be found in other reviews [92,96].…”

A hydrophobic funnel governs monovalent cation selectivity in the ion channel TRPM5

“…Within the TRP channel superfamily, TRPM (transient receptor potential melastatin) channels form the largest subfamily, consisting of eight members (TRPM1-8) ( Nilius and Owsianik, 2011 ; Samanta et al, 2018 ). TRPM channels assemble as homotetramers, in which each subunit provides six transmembrane helices (S1-S6), a cytosolic N -terminus domain composed of four melastatin homology regions, and a cytosolic C -terminus coiled-coil domain ( Hilton et al, 2019 ; van Goor et al, 2020 ). In keeping with most members of the TRP superfamily, TRPM channels are described as being cation non-selective, that is, they conduct cations but do not differentiate substantially between cationic species.…”