부산대학교 도서관

Transient receptor potential (TRP) ion channels are involved in the surveillance or regulation of the acid-base balance. Here, we demonstrate that weak carbonic acids, including acetic acid, lactic acid, and CO2 activate and sensitize TRPV2 through a mechanism requiring permeation through the cell membrane. TRPV2 channels in cell-free inside-out patches maintain weak acid-sensitivity, but protons applied on either side of the membrane do not induce channel activation or sensitization. The involvement of proton modulation sites for weak acid-sensitivity was supported by the identification of titratable extracellular (Glu495, Glu561) and intracellular (His521) residues on a cryo-EM structure of rat TRPV2 (rTRPV2) treated with acetic acid. Molecular dynamics simulations as well as patch clamp experiments on mutant rTRPV2 constructs confirmed that these residues are critical for weak acid-sensitivity. We also demonstrate that the pore residue Glu609 dictates an inhibition of weak acid-induced currents by extracellular calcium. Finally, TRPV2-expression in HEK293 cells is associated with an increased weak acid-induced cytotoxicity. Together, our data provide new insights into weak acids as endogenous modulators of TRPV2.
Synopsis: The transient receptor potential vanilloid 2 (TRPV2) ion channel controls important physiological and pathophysiological processes, but its regulation by acid species remains unclear. Here, combined structure-function work uncovers activation of rat TRPV2 by endogenous weak acids and offers a detailed characterization of its membrane permeation-dependent acid sensitivity.Weak, but not strong acids activate and sensitize TRPV2.Membrane permeability of weak acids is required for TRPV2 activation.Positively charged S4-S5 linker residue His521 controls TRPV2 weak acid-sensitivity.Extracellular calcium inhibits weak acid-induced TRPV2 activation.
Weak acetic acids are endogenous agonists of rat TRPV2 acting via permeation through the cell membrane.