Functional determinants of lysophospholipid- and voltage-dependent regulation of TRPC5 channel

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F24%3A00598345" target="_blank" >RIV/67985823:_____/24:00598345 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11310/24:10483767 RIV/00216208:11320/24:10483767
Result on the web
<a href="https://doi.org/10.1007/s00018-024-05417-7" target="_blank" >https://doi.org/10.1007/s00018-024-05417-7</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1007/s00018-024-05417-7" target="_blank" >10.1007/s00018-024-05417-7</a>

Result language
angličtina
Original language name
Functional determinants of lysophospholipid- and voltage-dependent regulation of TRPC5 channel
Original language description
Lysophosphatidylcholine (LPC) is a bioactive lipid present at high concentrations in inflamed and injured tissues where it contributes to the initiation and maintenance of pain. One of its important molecular effectors is the transient receptor potential canonical 5 (TRPC5), but the explicit mechanism of the activation is unknown. Using electrophysiology, mutagenesis and molecular dynamics simulations, we show that LPC-induced activation of TRPC5 is modulated by xanthine ligands and depolarizing voltage, and involves conserved residues within the lateral fenestration of the pore domain. Replacement of W577 with alanine (W577A) rendered the channel insensitive to strong depolarizing voltage, but LPC still activated this mutant at highly depolarizing potentials. Substitution of G606 located directly opposite position 577 with tryptophan rescued the sensitivity of W577A to depolarization. Molecular simulations showed that depolarization widens the lower gate of the channel and this conformational change is prevented by the W577A mutation or removal of resident lipids. We propose a gating scheme in which depolarizing voltage and lipid-pore helix interactions act together to promote TRPC5 channel opening.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30103 - Neurosciences (including psychophysiology)

Project
<a href="/en/project/GA22-13750S" target="_blank" >GA22-13750S: Signaling pathways affecting human TRPC5 receptor function: Prediction of their association with rheumatoid arthritis pain</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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