Molecular basis of inhibition of acid sensing ion channel 1A by diminazene

PloS One
Aram J KrausonMarcelo D Carattino

Abstract

Acid-sensing ion channels (ASICs) are trimeric proton-gated cation permeable ion channels expressed primarily in neurons. Here we employed site-directed mutagenesis and electrophysiology to investigate the mechanism of inhibition of ASIC1a by diminazene. This compound inhibits mouse ASIC1a with a half-maximal inhibitory concentration (IC50) of 2.4 μM. At first, we examined whether neutralizing mutations of Glu79 and Glu416 alter diminazene block. These residues form a hexagonal array in the lower palm domain that was previously shown to contribute to pore opening in response to extracellular acidification. Significantly, single Gln substitutions at positions 79 and 416 in ASIC1a reduced diminazene apparent affinity by 6-7 fold. This result suggests that diminazene inhibits ASIC1a in part by limiting conformational rearrangement in the lower palm domain. Because diminazene is charged at physiological pHs, we assessed whether it inhibits ASIC1a by blocking the ion channel pore. Consistent with the notion that diminazene binds to a site within the membrane electric field, diminazene block showed a strong dependence with the membrane potential. Moreover, a Gly to Ala mutation at position 438, in the ion conduction pathway of ASIC1a...Continue Reading

References

Apr 5, 1996·The Journal of Biological Chemistry·M P PriceM J Welsh
Feb 18, 1997·Proceedings of the National Academy of Sciences of the United States of America·J García-AñoverosD P Corey
Aug 26, 1998·Proceedings of the National Academy of Sciences of the United States of America·C C ChenJ N Wood
Sep 25, 1999·The Journal of Biological Chemistry·P M SnyderD B Bucher
Jun 1, 2000·The Journal of Biological Chemistry·P EscoubasM Lazdunski
Jun 14, 2000·Neuroreport·S GründerJ P Ruppersberg
Aug 3, 2000·Neuroreport·A N AkopianJ N Wood
Jul 13, 2001·The Journal of Biological Chemistry·E L BässlerS Gründer
Jun 13, 2002·Proceedings of the National Academy of Sciences of the United States of America·Chih-Cheng ChenAndreas Zimmer
Jun 28, 2002·Physiological Reviews·Stephan Kellenberger, Laurent Schild
Feb 14, 2003·The Journal of Biological Chemistry·Bakhrom K BerdievDale J Benos
Jul 16, 2004·American Journal of Physiology. Cell Physiology·James K BubienDale J Benos
May 24, 2005·The Journal of Biological Chemistry·Ossama B KashlanThomas R Kleyman
Mar 1, 2006·The Journal of General Physiology·Xuanmao ChenStefan Gründer
May 18, 2006·The Journal of Biological Chemistry·Wanda H Vila-CarrilesDale J Benos
Oct 25, 2006·Proceedings of the National Academy of Sciences of the United States of America·Xiang-ming ZhaMichael J Welsh
Sep 11, 2007·Biochemical and Biophysical Research Communications·Shinya UgawaShoichi Shimada
Apr 16, 2008·Journal of Neurochemistry·Natalia A DorofeevaLev G Magazanik
Jul 9, 2008·Neurobiology of Disease·Robert L AriasMichael Monaghan
Feb 2, 2010·Neuropharmacology·Xuanmao ChenJohn F MacDonald
Mar 11, 2011·The Journal of Biological Chemistry·Lindsey A TolinoMarcelo D Carattino
Mar 1, 2012·The Journal of Biological Chemistry·Marcelo D Carattino, Margaret C Della Vecchia
Oct 31, 2012·Annals of Neurology·Philip R HollandPeter J Goadsby
Jan 10, 2013·The Journal of Biological Chemistry·Margaret C Della VecchiaMarcelo D Carattino
Jun 21, 2013·Nature Reviews. Neuroscience·John A WemmieCollin J Kreple
Oct 22, 2013·The Journal of Biological Chemistry·Aram J KrausonMarcelo D Carattino
Feb 19, 2016·CNS Neuroscience & Therapeutics·Tian-Dong LengZhi-Gang Xiong
Oct 14, 2017·Molecular Pharmacology·Axel SchmidtStefan Gründer

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Citations

Jun 11, 2019·Synapse·Osvaldo D UchitelCarina Weissmann
Apr 19, 2019·ACS Medicinal Chemistry Letters·Leda Ivanova BenchevaRomano Di Fabio
Nov 27, 2018·ACS Chemical Neuroscience·Maxim V NikolaevDenis B Tikhonov

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