Deciphering the regulation of P2X4 receptor channel gating by ivermectin using Markov models

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F17%3A00477230" target="_blank" >RIV/67985823:_____/17:00477230 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1371/journal.pcbi.1005643" target="_blank" >http://dx.doi.org/10.1371/journal.pcbi.1005643</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1371/journal.pcbi.1005643" target="_blank" >10.1371/journal.pcbi.1005643</a>

Result language

angličtina

Original language name

Deciphering the regulation of P2X4 receptor channel gating by ivermectin using Markov models

Original language description

The P2X4 receptor (P2X4R) is a member of a family of purinergic channels activated by extracellular ATP through three orthosteric binding sites and allosterically regulated by ivermectin (IVM), a broad-spectrum antiparasitic agent. Treatment with IVM increases the efficacy of ATP to activate P2X4R, slows both receptor desensitization during sustained ATP application and receptor deactivation after ATP washout, and makes the receptor pore permeable to NMDG+, a large organic cation. Previously, we developed a Markov model based on the presence of one IVM binding site, which described some effects of IVM on rat P2X4R. Here we present two novel models, both with three IVM binding sites. The simpler one-layer model can reproduce many of the observed time series of evoked currents, but does not capture well the short time scales of activation, desensitization, and deactivation. A more complex two-layer model can reproduce the transient changes in desensitization observed upon IVM application, the significant increase in ATP-induced current amplitudes at low IVM concentrations, and the modest increase in the unitary conductance. In addition, the two-layer model suggests that this receptor can exist in a deeply inactivated state, not responsive to ATP, and that its desensitization rate can be altered by each of the three IVM binding sites. In summary, this study provides a detailed analysis of P2X4R kinetics and elucidates the orthosteric and allosteric mechanisms regulating its channel gating.

Czech name

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Czech description

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Type

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

CEP classification

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OECD FORD branch

30105 - Physiology (including cytology)

Project

<a href="/en/project/GBP304%2F12%2FG069" target="_blank" >GBP304/12/G069: Project of excellence in the field of neuroscience</a><br>

Continuities

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

Publication year

2017

Confidentiality

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

Name of the periodical

PLoS Computational Biology

ISSN

1553-734X

e-ISSN

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Volume of the periodical

13

Issue of the periodical within the volume

7

Country of publishing house

US - UNITED STATES

Number of pages

27

Pages from-to

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UT code for WoS article

000406619800029

EID of the result in the Scopus database

2-s2.0-85026642231