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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F22%3A00559165" target="_blank" >RIV/67985823:_____/22:00559165 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11310/22:10452949

Result on the web

<a href="https://doi.org/10.1016/j.biopha.2022.113262" target="_blank" >https://doi.org/10.1016/j.biopha.2022.113262</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.biopha.2022.113262" target="_blank" >10.1016/j.biopha.2022.113262</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30105 - Physiology (including cytology)

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

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Biomedicine & Pharmacotherapy

ISSN

0753-3322

e-ISSN

1950-6007

Volume of the periodical

152

Issue of the periodical within the volume

August

Country of publishing house

FR - FRANCE

Number of pages

11

Pages from-to

113262

UT code for WoS article

000815801200004

EID of the result in the Scopus database

2-s2.0-85132316348