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Synthetic testosterone derivatives modulate rat P2X2 and P2X4 receptor channel gating
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SYSNO ASEP 0507827 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Synthetic testosterone derivatives modulate rat P2X2 and P2X4 receptor channel gating Author(s) Sivčev, Sonja (FGU-C) RID, ORCID
Slavíková, Barbora (UOCHB-X) RID, ORCID
Rupert, Marian (FGU-C) RID, ORCID, SAI
Ivetic, Milorad (FGU-C) RID, ORCID
Nekardová, Michaela (UOCHB-X) RID
Kudová, Eva (UOCHB-X) RID, ORCID
Zemková, Hana (FGU-C) RID, ORCIDSource Title Journal of Neurochemistry. - : Wiley - ISSN 0022-3042
Roč. 150, č. 1 (2019), s. 28-43Number of pages 16 s. Language eng - English Country US - United States Keywords allosteric modulation ; ATP ; P2XR ; testosterone derivatives ; purinergic receptors ; ivermectin Subject RIV FH - Neurology OECD category Neurosciences (including psychophysiology R&D Projects GA16-12695S GA ČR - Czech Science Foundation (CSF) GA18-05413S GA ČR - Czech Science Foundation (CSF) GBP208/12/G016 GA ČR - Czech Science Foundation (CSF) LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access with time embargo (01.07.2020) Institutional support FGU-C - RVO:67985823 ; UOCHB-X - RVO:61388963 UT WOS 000472767700002 EID SCOPUS 85067474971 DOI 10.1111/jnc.14718 Annotation P2X receptors (P2XRs) are ATP-gated cationic channels that are allosterically modulated by numerous compounds, including steroids and neurosteroids. These compounds may both inhibit and potentiate the activity of P2XRs, but sex steroids such as 17 beta-estradiol or progesterone are reported to be inactive. Here, we tested a hypothesis that testosterone, another sex hormone, modulates activity of P2XRs. We examined actions of native testosterone and a series of testosterone derivatives on the gating of recombinant P2X2R, P2X4R and P2X7R and native channels expressed in pituitary cells and hypothalamic neurons. The 17 beta-ester derivatives of testosterone rapidly and positively modulate the 1 mu M ATP-evoked currents in P2X2R- and P2X4R-expressing cells, but not agonist-evoked currents in P2X7R-expressing cells. In general, most of the tested testosterone derivatives are more potent modulators than endogenous testosterone. The comparison of chemical structures and whole-cell recordings revealed that their interactions with P2XRs depend on the lipophilicity and length of the alkyl chain at position C-17. Pre-treatment with testosterone butyrate or valerate increases the sensitivity of P2X2R and P2X4R to ATP by several fold, reduces the rate of P2X4R desensitization, accelerates resensitization, and enhances ethidium uptake by P2X4R. Native channels are also potentiated by testosterone derivatives, while endogenously expressed GABA receptors type A are inhibited. The effect of ivermectin, a P2X4R-specific allosteric modulator, on deactivation is antagonized by testosterone derivatives in a concentration-dependent manner. Together, our results provide evidence for potentiation of particular subtypes of P2XRs by testosterone derivatives and suggest a potential role of ivermectin binding site for steroid-induced modulation. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2020 Electronic address https://doi.org/10.1111/jnc.14718
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