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

Autor:	Matasic DS; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, IA, United States.; Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States., Holland N; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, IA, United States.; Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, United States., Gautam M; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, IA, United States.; Iowa City VA Healthcare System, Iowa City, IA, United States., Gibbons DD; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, IA, United States.; Iowa City VA Healthcare System, Iowa City, IA, United States., Kusama N; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, IA, United States.; Iowa City VA Healthcare System, Iowa City, IA, United States., Harding AMS; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, IA, United States.; Iowa City VA Healthcare System, Iowa City, IA, United States., Shah VS; Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States., Snyder PM; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, IA, United States.; Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States.; Iowa City VA Healthcare System, Iowa City, IA, United States., Benson CJ; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, IA, United States.; Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, United States.; Iowa City VA Healthcare System, Iowa City, IA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in physiology [Front Physiol] 2021 Oct 15; Vol. 12, pp. 750696. Date of Electronic Publication: 2021 Oct 15 (Print Publication: 2021).
DOI:	10.3389/fphys.2021.750696
Abstrakt:	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 Ca 2+ 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, Ca 2+ , and protons at probably more than one site in the channel. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Matasic, Holland, Gautam, Gibbons, Kusama, Harding, Shah, Snyder and Benson.)
Databáze:	MEDLINE
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