Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a)

Abstract Acid-Sensing Ion Channels (ASICs) are gated by extracellular protons and play important roles in physiological and pathological states, such as pain and stroke. ASIC1a and ASIC2a, two of the most highly expressed subunits in the brain, form functional homo- and hetero-meric (ASIC1a/2a) chan...

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Autores principales:	Yi Liu, Rebecca Hagan, Jeffrey Schoellerman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6ecfee660a634987bfb6e194583a7b0a
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spelling	oai:doaj.org-article:6ecfee660a634987bfb6e194583a7b0a2021-12-02T12:32:10ZDual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a)10.1038/s41598-018-25386-92045-2322https://doaj.org/article/6ecfee660a634987bfb6e194583a7b0a2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25386-9https://doaj.org/toc/2045-2322Abstract Acid-Sensing Ion Channels (ASICs) are gated by extracellular protons and play important roles in physiological and pathological states, such as pain and stroke. ASIC1a and ASIC2a, two of the most highly expressed subunits in the brain, form functional homo- and hetero-meric (ASIC1a/2a) channels. The function of ASIC1a has been widely studied using psalmotoxin (PcTx1), a venom-derived peptide, as an ASIC1a-selective antagonist. Here, using whole-cell patch clamp, we show that PcTx1 has dual actions at ASIC1a/2a. It can either inhibit or potentiate the heteromeric channel, depending on the conditioning and stimulating pHs. Potent inhibition occurs only at conditioning pHs that begin to desensitize the channel (IC50 = 2.9 nM at pH7.0, a threshold pH for desensitization of ASIC1a/2a). By contrast, potent potentiation can occur at the physiological pH in both CHO cells (EC50 = 56.1 nM) and cortical neurons (threshold concentration < 10 nM). PcTx1 potentiates ASIC1a/2a by increasing the apparent affinity of channel activation for protons. As such, potentiation is the strongest at moderate pHs, diminishing with increasing proton concentrations. Our findings identify PcTx1 as a valuable tool for studying ASIC1a/2a function and contribute significantly to the understanding of the diverse and complex pharmacology of PcTx1.Yi LiuRebecca HaganJeffrey SchoellermanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yi Liu Rebecca Hagan Jeffrey Schoellerman Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a)
description	Abstract Acid-Sensing Ion Channels (ASICs) are gated by extracellular protons and play important roles in physiological and pathological states, such as pain and stroke. ASIC1a and ASIC2a, two of the most highly expressed subunits in the brain, form functional homo- and hetero-meric (ASIC1a/2a) channels. The function of ASIC1a has been widely studied using psalmotoxin (PcTx1), a venom-derived peptide, as an ASIC1a-selective antagonist. Here, using whole-cell patch clamp, we show that PcTx1 has dual actions at ASIC1a/2a. It can either inhibit or potentiate the heteromeric channel, depending on the conditioning and stimulating pHs. Potent inhibition occurs only at conditioning pHs that begin to desensitize the channel (IC50 = 2.9 nM at pH7.0, a threshold pH for desensitization of ASIC1a/2a). By contrast, potent potentiation can occur at the physiological pH in both CHO cells (EC50 = 56.1 nM) and cortical neurons (threshold concentration < 10 nM). PcTx1 potentiates ASIC1a/2a by increasing the apparent affinity of channel activation for protons. As such, potentiation is the strongest at moderate pHs, diminishing with increasing proton concentrations. Our findings identify PcTx1 as a valuable tool for studying ASIC1a/2a function and contribute significantly to the understanding of the diverse and complex pharmacology of PcTx1.
format	article
author	Yi Liu Rebecca Hagan Jeffrey Schoellerman
author_facet	Yi Liu Rebecca Hagan Jeffrey Schoellerman
author_sort	Yi Liu
title	Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a)
title_short	Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a)
title_full	Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a)
title_fullStr	Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a)
title_full_unstemmed	Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a)
title_sort	dual actions of psalmotoxin at asic1a and asic2a heteromeric channels (asic1a/2a)
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/6ecfee660a634987bfb6e194583a7b0a
work_keys_str_mv	AT yiliu dualactionsofpsalmotoxinatasic1aandasic2aheteromericchannelsasic1a2a AT rebeccahagan dualactionsofpsalmotoxinatasic1aandasic2aheteromericchannelsasic1a2a AT jeffreyschoellerman dualactionsofpsalmotoxinatasic1aandasic2aheteromericchannelsasic1a2a
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Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a)

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