Activity dependent inhibition of TRPC1/4/5 channels by duloxetine involves voltage sensor-like domain

0559165 - FGÚ 2023 RIV FR eng J - Článek v odborném periodiku
Zímová, Lucie - Ptáková, Alexandra - Mitro, Michal - Krůšek, Jan - Vlachová, Viktorie
Activity dependent inhibition of TRPC1/4/5 channels by duloxetine involves voltage sensor-like domain.
Biomedicine & Pharmacotherapy. Roč. 152, August (2022), č. článku 113262. ISSN 0753-3322. E-ISSN 1950-6007
Grant CEP: GA ČR(CZ) GA22-13750S
Institucionální podpora: RVO:67985823
Klíčová slova: TRPC channels * TRPC5 * Duloxetine * inhibitor * voltage sensor-like domain
Obor OECD: Physiology (including cytology)
Impakt faktor: 7.5, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1016/j.biopha.2022.113262

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.
Trvalý link: https://hdl.handle.net/11104/0332574