Unravelling the intricate cooperativity of subunit gating in P2X2 ion channels

Abstract Ionotropic purinergic (P2X) receptors are trimeric channels that are activated by the binding of ATP. They are involved in multiple physiological functions, including synaptic transmission, pain and inflammation. The mechanism of activation is still elusive. Here we kinetically unraveled an...

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Autores principales:	Christian Sattler, Thomas Eick, Sabine Hummert, Eckhard Schulz, Ralf Schmauder, Andrea Schweinitz, Christopher Unzeitig, Frank Schwede, Klaus Benndorf
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1df92b225dd244dcb0623e62c017f5d8
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spelling	oai:doaj.org-article:1df92b225dd244dcb0623e62c017f5d82021-12-02T16:18:03ZUnravelling the intricate cooperativity of subunit gating in P2X2 ion channels10.1038/s41598-020-78672-w2045-2322https://doaj.org/article/1df92b225dd244dcb0623e62c017f5d82020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78672-whttps://doaj.org/toc/2045-2322Abstract Ionotropic purinergic (P2X) receptors are trimeric channels that are activated by the binding of ATP. They are involved in multiple physiological functions, including synaptic transmission, pain and inflammation. The mechanism of activation is still elusive. Here we kinetically unraveled and quantified subunit activation in P2X2 receptors by an extensive global fit approach with four complex and intimately coupled kinetic schemes to currents obtained from wild type and mutated receptors using ATP and its fluorescent derivative 2-[DY-547P1]-AET-ATP (fATP). We show that the steep concentration-activation relationship in wild type channels is caused by a subunit flip reaction with strong positive cooperativity, overbalancing a pronounced negative cooperativity for the three ATP binding steps, that the net probability fluxes in the model generate a marked hysteresis in the activation-deactivation cycle, and that the predicted fATP binding matches the binding measured by fluorescence. Our results shed light into the intricate activation process of P2X channels.Christian SattlerThomas EickSabine HummertEckhard SchulzRalf SchmauderAndrea SchweinitzChristopher UnzeitigFrank SchwedeKlaus BenndorfNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christian Sattler Thomas Eick Sabine Hummert Eckhard Schulz Ralf Schmauder Andrea Schweinitz Christopher Unzeitig Frank Schwede Klaus Benndorf Unravelling the intricate cooperativity of subunit gating in P2X2 ion channels
description	Abstract Ionotropic purinergic (P2X) receptors are trimeric channels that are activated by the binding of ATP. They are involved in multiple physiological functions, including synaptic transmission, pain and inflammation. The mechanism of activation is still elusive. Here we kinetically unraveled and quantified subunit activation in P2X2 receptors by an extensive global fit approach with four complex and intimately coupled kinetic schemes to currents obtained from wild type and mutated receptors using ATP and its fluorescent derivative 2-[DY-547P1]-AET-ATP (fATP). We show that the steep concentration-activation relationship in wild type channels is caused by a subunit flip reaction with strong positive cooperativity, overbalancing a pronounced negative cooperativity for the three ATP binding steps, that the net probability fluxes in the model generate a marked hysteresis in the activation-deactivation cycle, and that the predicted fATP binding matches the binding measured by fluorescence. Our results shed light into the intricate activation process of P2X channels.
format	article
author	Christian Sattler Thomas Eick Sabine Hummert Eckhard Schulz Ralf Schmauder Andrea Schweinitz Christopher Unzeitig Frank Schwede Klaus Benndorf
author_facet	Christian Sattler Thomas Eick Sabine Hummert Eckhard Schulz Ralf Schmauder Andrea Schweinitz Christopher Unzeitig Frank Schwede Klaus Benndorf
author_sort	Christian Sattler
title	Unravelling the intricate cooperativity of subunit gating in P2X2 ion channels
title_short	Unravelling the intricate cooperativity of subunit gating in P2X2 ion channels
title_full	Unravelling the intricate cooperativity of subunit gating in P2X2 ion channels
title_fullStr	Unravelling the intricate cooperativity of subunit gating in P2X2 ion channels
title_full_unstemmed	Unravelling the intricate cooperativity of subunit gating in P2X2 ion channels
title_sort	unravelling the intricate cooperativity of subunit gating in p2x2 ion channels
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/1df92b225dd244dcb0623e62c017f5d8
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Unravelling the intricate cooperativity of subunit gating in P2X2 ion channels

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