Pharmacological modulation of Acid-Sensing Ion Channels 1a and 3 by amiloride and 2-guanidine-4-methylquinazoline (GMQ)

Acid-Sensing Ion Channels (ASICs) are cation channels activated by extracellular acidification that emerge as potential pharmacological targets in pain and other neurological disorders. Here, we compare the pharmacological modulation of ASIC1a and ASIC3 channels by amiloride and 2-guanidine-4-methyl...

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Bibliographic Details
Published in:Neuropharmacology 2017-10, Vol.125, p.429-440
Main Authors: Besson, Thomas, Lingueglia, Eric, Salinas, Miguel
Format: Article
Language:English
Subjects:
Acid Sensing Ion Channel Blockers - pharmacology
Acid Sensing Ion Channels - metabolism
Acid-Sensing Ion Channel (ASIC)
Amiloride
Amiloride - pharmacology
Animals
Elapid Venoms - pharmacology
GMQ
Guanidines - pharmacology
Hydrogen-Ion Concentration
Life Sciences
Mambalgin
Membrane Potentials - drug effects
Membrane Potentials - physiology
Neurobiology
Neurons and Cognition
Oocytes
PcTx1
Peptides - pharmacology
pH-dependent gating
Pharmaceutical sciences
Pharmacology
Protein Domains
Quinazolines - pharmacology
Rats
Recombinant Fusion Proteins - metabolism
Spider Venoms - pharmacology
Xenopus
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Summary:Acid-Sensing Ion Channels (ASICs) are cation channels activated by extracellular acidification that emerge as potential pharmacological targets in pain and other neurological disorders. Here, we compare the pharmacological modulation of ASIC1a and ASIC3 channels by amiloride and 2-guanidine-4-methylquinazoline (GMQ), two compounds commonly used for their in vitro and in vivo investigation. We analyzed the effect of amiloride on the pH-dependent activation and inactivation, the relative influence of the extracellular domain and the transmembrane/cytosolic domains on the effect of amiloride and GMQ using chimeras between ASIC1a and ASIC3, and how these compounds potentiate the physiologically relevant ASIC3 sustained window current. We showed that amiloride and GMQ shift the pH-dependent activation and inactivation in the same directions, which depend on the channel, and that their effects rely on the nature of the extracellular domain but can be indirectly modulated in their amplitude by the transmembrane/cytosolic domains. The extracellular domain explains the pharmacological potentiating effect of amiloride and GMQ on the window current in ASIC3, and why these compounds failed to generate a window current in ASIC1a. Amiloride and GMQ have similar and purely additive effects suggesting that they act through a common unique binding site different from acidic pockets. Finally, a simple cycle analysis using GMQ that targets the nonproton ligand-sensor, and two peptide inhibitors of ASIC1a targeting the acidic pockets (PcTx1 and mambalgin-1), shows overlap between the mechanisms by which GMQ and PcTx1 modify inactivation and suggests shared mechanisms of regulation of the pH-dependent inactivation of ASIC1a between these two regions. •First direct comparison of the effect of amiloride (AMI) and GMQ on ASICs.•Gating regulation by AMI and GMQ depends on the nature of the extracellular domain.•The transmembrane/cytosolic domains modulate the pharmacological regulation of ASICs.•Additive effect of AMI and GMQ fits well with a common unique binding site.•Mechanisms of gating regulation by GMQ & PcTx1, but not mambalgin, partially overlap.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2017.08.004