Počet záznamů: 1
Activity dependent inhibition of TRPC1/4/5 channels by duloxetine involves voltage sensor-like domain
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SYSNO ASEP 0559165 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Activity dependent inhibition of TRPC1/4/5 channels by duloxetine involves voltage sensor-like domain Tvůrce(i) Zímová, Lucie (FGU-C) RID, ORCID
Ptáková, Alexandra (FGU-C) RID, ORCID
Mitro, Michal (FGU-C)
Krůšek, Jan (FGU-C) RID, ORCID
Vlachová, Viktorie (FGU-C) RID, ORCID, SAIČíslo článku 113262 Zdroj.dok. Biomedicine & Pharmacotherapy. - : Elsevier - ISSN 0753-3322
Roč. 152, August (2022)Poč.str. 11 s. Jazyk dok. eng - angličtina Země vyd. FR - Francie Klíč. slova TRPC channels ; TRPC5 ; Duloxetine ; inhibitor ; voltage sensor-like domain Obor OECD Physiology (including cytology) CEP GA22-13750S GA ČR - Grantová agentura ČR Způsob publikování Open access Institucionální podpora FGU-C - RVO:67985823 UT WOS 000815801200004 EID SCOPUS 85132316348 DOI https://doi.org/10.1016/j.biopha.2022.113262 Anotace Transient receptor potential canonical 5 (TRPC5) is a polymodal, calcium-permeable, nonselective ion channel that is expressed in the brain and 75 % of human sensory neurons. Its pharmacological or genetic inhibition leads to the relief of neuropathic and inflammatory pain. The clinically approved drug duloxetine is superior to other serotonin and norepinephrine reuptake inhibitors at managing painful neuropathies, but it is not known why. Here we ask whether the TRPC5 receptor is modulated by duloxetine and may contribute to its analgesic effect. Electrophysiological measurements of heterologously expressed human TRPC5 in HEK293T cells were performed to evaluate the effect of duloxetine. The interaction site was identified by molecular docking and molecular dynamics simulations in combination with point mutagenesis. We found that duloxetine inhibits TRPC5 in a concentration-dependent manner with a high potency (IC50 = 0.54 ± 0.03 µM). Our data suggest that duloxetine binds into a voltage sensor-like domain. For the interaction, Glu418 exhibited particular importance due to putative hydrogen bond formation. Duloxetine effectively inhibits TRPC5 currents induced by cooling, voltage, direct agonists and by the stimulation of the PLC pathway. The finding that this TRPC5 inhibitor is widely used and well tolerated provides a scaffold for new pain treatment strategies. Pracoviště Fyziologický ústav Kontakt Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Rok sběru 2023 Elektronická adresa https://doi.org/10.1016/j.biopha.2022.113262
Počet záznamů: 1