ASIC1a-specific modulation of acid-sensing ion channels in mouse cortical neurons by redox reagents

Xiang Ping Chu, Natasha Close, Julie Saugstad, Zhi Gang Xiong

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Acid-sensing ion channel (ASIC)-1a, the major ASIC subunit with Ca 2+ permeability, is highly expressed in the neurons of CNS. Activation of these channels with resultant intracellular Ca2+ accumulation plays a critical role in normal synaptic plasticity, learning/memory, and in acidosis-mediated glutamate receptor-independent neuronal injury. Here we demonstrate that the activities of ASICs in CNS neurons are tightly regulated by the redox state of the channels and that the modulation is ASIC1a subunit dependent. In cultured mouse cortical neurons, application of the reducing agents dramatically potentiated, whereas the oxidizing agents inhibited the ASIC currents. However, in neurons from the ASIC1 knock-out mice, neither oxidizing agents nor reducing reagents had any effect on the acid-activated current. In Chinese Hamster Ovary cells, redox-modifying agents only affected the current mediated by homomeric ASIC1a, but not homomeric ASIC1b, ASIC2a, or ASIC3. In current-clamp recordings and Ca 2+-imaging experiments, the reducing agents increased but the oxidizing agents decreased acid-induced membrane depolarization and the intracellular Ca2+ accumulation. Site-directed mutagenesis studies identified involvement of cysteine 61 and lysine 133, located in the extracellular domain of the ASIC1a subunit, in the modulation of ASICs by oxidizing and reducing agents, respectively. Our results suggest that redox state of the ASIC1a subunit is an important factor in determining the overall physiological function and the pathological role of ASICs in the CNS.

Original languageEnglish (US)
Pages (from-to)5329-5339
Number of pages11
JournalJournal of Neuroscience
Volume26
Issue number20
DOIs
StatePublished - 2006
Externally publishedYes

Fingerprint

Acid Sensing Ion Channels
Oxidants
Oxidation-Reduction
Reducing Agents
Neurons
Intracellular Membranes
Neuronal Plasticity
Acids
Glutamate Receptors
Site-Directed Mutagenesis
Acidosis
Cricetulus
Knockout Mice
Lysine
Cysteine
Ovary
Permeability
Learning
Wounds and Injuries

Keywords

  • ASIC1a
  • Ischemia
  • Neuronal injury
  • Oxidizing/reducing agent
  • Patch-clamp
  • Redox reagents

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

ASIC1a-specific modulation of acid-sensing ion channels in mouse cortical neurons by redox reagents. / Chu, Xiang Ping; Close, Natasha; Saugstad, Julie; Xiong, Zhi Gang.

In: Journal of Neuroscience, Vol. 26, No. 20, 2006, p. 5329-5339.

Research output: Contribution to journalArticle

Chu, Xiang Ping ; Close, Natasha ; Saugstad, Julie ; Xiong, Zhi Gang. / ASIC1a-specific modulation of acid-sensing ion channels in mouse cortical neurons by redox reagents. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 20. pp. 5329-5339.
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AB - Acid-sensing ion channel (ASIC)-1a, the major ASIC subunit with Ca 2+ permeability, is highly expressed in the neurons of CNS. Activation of these channels with resultant intracellular Ca2+ accumulation plays a critical role in normal synaptic plasticity, learning/memory, and in acidosis-mediated glutamate receptor-independent neuronal injury. Here we demonstrate that the activities of ASICs in CNS neurons are tightly regulated by the redox state of the channels and that the modulation is ASIC1a subunit dependent. In cultured mouse cortical neurons, application of the reducing agents dramatically potentiated, whereas the oxidizing agents inhibited the ASIC currents. However, in neurons from the ASIC1 knock-out mice, neither oxidizing agents nor reducing reagents had any effect on the acid-activated current. In Chinese Hamster Ovary cells, redox-modifying agents only affected the current mediated by homomeric ASIC1a, but not homomeric ASIC1b, ASIC2a, or ASIC3. In current-clamp recordings and Ca 2+-imaging experiments, the reducing agents increased but the oxidizing agents decreased acid-induced membrane depolarization and the intracellular Ca2+ accumulation. Site-directed mutagenesis studies identified involvement of cysteine 61 and lysine 133, located in the extracellular domain of the ASIC1a subunit, in the modulation of ASICs by oxidizing and reducing agents, respectively. Our results suggest that redox state of the ASIC1a subunit is an important factor in determining the overall physiological function and the pathological role of ASICs in the CNS.

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