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TitleFunctional and structural insights into activation of TRPV2 by weak acids.
Journal, issue, pagesEMBO J, Year 2024
Publish dateApr 26, 2024
AuthorsFerdinand M Haug / Ruth A Pumroy / Akshay Sridhar / Sebastian Pantke / Florian Dimek / Tabea C Fricke / Axel Hage / Christine Herzog / Frank G Echtermeyer / Jeanne de la Roche / Adrian Koh / Abhay Kotecha / Rebecca J Howard / Erik Lindahl / Vera Moiseenkova-Bell / Andreas Leffler /
PubMed AbstractTransient 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 ...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 CO 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.
External linksEMBO J / PubMed:38671253
MethodsEM (single particle)
Resolution2.6 - 3.1 Å
Structure data

28209

8ekp

EMDB-28209, PDB-8ekp:
Apo rat TRPV2 in nanodiscs, state 1
Method: EM (single particle) / Resolution: 2.75 Å

28210

8ekq

EMDB-28210, PDB-8ekq:
Apo rat TRPV2 in nanodiscs, state 2
Method: EM (single particle) / Resolution: 2.6 Å

28211

8ekr

EMDB-28211, PDB-8ekr:
Apo rat TRPV2 in nanodiscs, state 3
Method: EM (single particle) / Resolution: 3.0 Å

28212

8eks

EMDB-28212, PDB-8eks:
rat TRPV2 in nanodiscs in the presence of weak acid at pH 5
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-PEX:
1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE

Source
  • rattus norvegicus (Norway rat)
KeywordsTRANSPORT PROTEIN / Ion channel / TRP channel / Membrane protein / tetramer

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