title: Quercetin inhibits acid-sensing ion channels through a putative binding site in the central vestibular region.
abstract: Acid-sensing ion channels (ASICs) are associated with many pathophysiological processes, such as neuronal death during ischemic stroke, epileptic seizure and nociception. However, there is a dearth of ASIC-specific therapeutic blockers. Here we report that quercetin, a plant flavonoid, which is known for its neuroprotective effect, reversibly inhibits homomeric rat ASIC1a, ASIC2a and ASIC3 with an IC50of about 2µM. Also, quercetin prevents low pH-induced intracellular calcium rise and cell death in HEK-293 cells, which have endogenous expression of ASIC1a and 2a. The inhibitory effect of quercetin on ASICs is not due to membrane perturbation, as it did not have any effect on other channels, like NMDA receptor, GABAAreceptor and P2X4 receptor. Unlike quercetin, another flavonoid resveratrol had no effect on ASIC1a. Computational analysis revealed that quercetin binds to the channel in a cavity at the central vestibule, lined by several charged residues like Q276, R369, E373 and E416 in ASIC1a. Mutation of Arg369 to Ala or Glu416 to Gln abolished the inhibitory effect of quercetin on rat ASIC1a completely, while Glu373 to Gln showed reduced sensitivity. Our results raise the possibility of using quercetin for targeting ASICs in vivo.
authors.affiliation: Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600036, India.
authors.forename: Mohona
authors.initials: M
authors.lastname: Mukhopadhyay
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER) Hajipur, Bihar, India.
authors.forename: Anurag
authors.initials: A
authors.lastname: Singh
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER) Hajipur, Bihar, India.
authors.forename: S
authors.initials: S
authors.lastname: Sachchidanand
authors.affiliation: Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600036, India. Electronic address: amal@iitm.ac.in.
authors.forename: Amal Kanti
authors.initials: AK
authors.lastname: Bera
mesh_terms: D062646:Acid Sensing Ion Channel Blockers / Q000494:pharmacology*; D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*
chemical_list: D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; D011794:Quercetin; D002118:Calcium
keywords: acid-sensing ion channel; flavonoid; ischemia; neuroprotection; quercetin; stroke