Paradoxical Potentiation of Acid-Sensing Ion Channel 3 (ASIC3) by Amiloride via Multiple Mechanisms and Sites Within the Channel

Daniel S. Matasic; Nicholas Holland; Mamta Gautam; David D. Gibbons; Nobuyoshi Kusama; Anne M. S. Harding; Viral S. Shah; Peter M. Snyder; Christopher J. Benson

doi:10.3389/fphys.2021.750696

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Paradoxical Potentiation of Acid-Sensing Ion Channel 3 (ASIC3) by Amiloride via Multiple Mechanisms and Sites Within the Channel

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Paradoxical Potentiation of Acid-Sensing Ion Channel 3 (ASIC3) by Amiloride via Multiple Mechanisms and Sites Within the Channel

Daniel S. Matasic, Nicholas Holland, Mamta Gautam, David D. Gibbons, Nobuyoshi Kusama, Anne M. S. Harding, Viral S. Shah, Peter M. Snyder and Christopher J. Benson

Frontiers in physiology, Vol.12, pp.750696-750696

10/15/2021

DOI: 10.3389/fphys.2021.750696

PMCID: PMC8555766

PMID: 34721074

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Abstract

Acid-Sensing Ion Channels (ASICs) are proton-gated sodium-selective cation channels that have emerged as metabolic and pain sensors in peripheral sensory neurons and contribute to neurotransmission in the CNS. These channels and their related degenerin/epithelial sodium channel (DEG/ENaC) family are often characterized by their sensitivity to amiloride inhibition. However, amiloride can also cause paradoxical potentiation of ASIC currents under certain conditions. Here we characterized and investigated the determinants of paradoxical potentiation by amiloride on ASIC3 channels. While inhibiting currents induced by acidic pH, amiloride potentiated sustained currents at neutral pH activation. These effects were accompanied by alterations in gating properties including (1) an alkaline shift of pH-dependent activation, (2) inhibition of pH-dependent steady-state desensitization (SSD), (3) prolongation of desensitization kinetics, and (4) speeding of recovery from desensitization. Interestingly, extracellular Ca2+ was required for paradoxical potentiation and it diminishes the amiloride-induced inhibition of SSD. Site-directed mutagenesis within the extracellular non-proton ligand-sensing domain (E79A, E423A) demonstrated that these residues were critical in mediating the amiloride-induced inhibition of SSD. However, disruption of the purported amiloride binding site (G445C) within the channel pore blunted both the inhibition and potentiation of amiloride. Together, our results suggest that the myriad of modulatory and blocking effects of amiloride are the result of a complex competitive interaction between amiloride, Ca2+, and protons at probably more than one site in the channel.

Life Sciences & Biomedicine

Physiology

Science & Technology

Details

Title: Subtitle: Paradoxical Potentiation of Acid-Sensing Ion Channel 3 (ASIC3) by Amiloride via Multiple Mechanisms and Sites Within the Channel
Creators: Daniel S. Matasic - University of Iowa
Nicholas Holland - University of Iowa
Mamta Gautam - University of Iowa
David D. Gibbons - University of Iowa
Nobuyoshi Kusama - University of Iowa
Anne M. S. Harding - University of Iowa
Viral S. Shah - University of Iowa
Peter M. Snyder - University of Iowa
Christopher J. Benson - University of Iowa
Resource Type: Journal article
Publication Details: Frontiers in physiology, Vol.12, pp.750696-750696
DOI: 10.3389/fphys.2021.750696
PMID: 34721074
PMCID: PMC8555766
NLM abbreviation: Front Physiol
ISSN: 1664-042X
eISSN: 1664-042X
Publisher: Frontiers Media Sa
Number of pages: 14
Grant note: 5I01BX000776 / Department of Veterans Affairs Merit Award; US Department of Veterans Affairs
Language: English
Date published: 10/15/2021
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Medicine Administration; Internal Medicine
Record Identifier: 9984297610902771

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