Mechanisms of Proton Inhibition and Sensitization of the Cation Channel TRPV3

The study investigated the mechanisms of acid regulation of the TRPV3 cation channel, which is important for hair morphogenesis and skin barrier function. Researchers found that extracellular acid inhibited TRPV3 activation through an aspartate residue (D641), while intracellular protons sensitized the channel via C-terminal glutamate and aspartate residues (E682, E689, and D727). Neutralizing these residues presensitized the channel to stimulation. Molecular simulations showed that this neutralization stabilized the channel's sensitized conformation. The findings suggested that acid could inhibit TRPV3 from outside the cell but enhance its function from inside, providing insights into TRPV3's role in skin disorders and epidermal barrier regulation under acidic conditions.