Identification of a unique Ca 2+ -binding site in rat acid-sensing ion channel 3

Zhicheng Zuo, Rachel N. Smith, Zhenglan Chen, Amruta S. Agharkar, Heather D. Snell, Ren-Qi Huang, Jin Liu, Eric B. Gonzales

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Acid-sensing ion channels (ASICs) evolved to sense changes in extracellular acidity with the divalent cation calcium (Ca 2+ ) as an allosteric modulator and channel blocker. The channel-blocking activity is most apparent in ASIC3, as removing Ca 2+ results in channel opening, with the site's location remaining unresolved. Here we show that a ring of rat ASIC3 (rASIC3) glutamates (Glu435), located above the channel gate, modulates proton sensitivity and contributes to the formation of the elusive Ca 2+ block site. Mutation of this residue to glycine, the equivalent residue in chicken ASIC1, diminished the rASIC3 Ca 2+ block effect. Atomistic molecular dynamic simulations corroborate the involvement of this acidic residue in forming a high-Affinity Ca 2+ site atop the channel pore. Furthermore, the reported observations provide clarity for past controversies regarding ASIC channel gating. Our findings enhance understanding of ASIC gating mechanisms and provide structural and energetic insights into this unique calcium-binding site.

Original languageEnglish
Article number2082
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018

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Acid Sensing Ion Channels
rats
Binding Sites
acids
Rats
Ion Channel Gating
Glutamates
Calcium
Divalent Cations
Molecular Dynamics Simulation
Acidity
Glycine
Modulators
Molecular dynamics
Protons
calcium
Chickens
chickens
Mutation
glutamates

Cite this

Zuo, Z., Smith, R. N., Chen, Z., Agharkar, A. S., Snell, H. D., Huang, R-Q., ... Gonzales, E. B. (2018). Identification of a unique Ca 2+ -binding site in rat acid-sensing ion channel 3 Nature Communications, 9(1), [2082]. https://doi.org/10.1038/s41467-018-04424-0
Zuo, Zhicheng ; Smith, Rachel N. ; Chen, Zhenglan ; Agharkar, Amruta S. ; Snell, Heather D. ; Huang, Ren-Qi ; Liu, Jin ; Gonzales, Eric B. / Identification of a unique Ca 2+ -binding site in rat acid-sensing ion channel 3 In: Nature Communications. 2018 ; Vol. 9, No. 1.
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abstract = "Acid-sensing ion channels (ASICs) evolved to sense changes in extracellular acidity with the divalent cation calcium (Ca 2+ ) as an allosteric modulator and channel blocker. The channel-blocking activity is most apparent in ASIC3, as removing Ca 2+ results in channel opening, with the site's location remaining unresolved. Here we show that a ring of rat ASIC3 (rASIC3) glutamates (Glu435), located above the channel gate, modulates proton sensitivity and contributes to the formation of the elusive Ca 2+ block site. Mutation of this residue to glycine, the equivalent residue in chicken ASIC1, diminished the rASIC3 Ca 2+ block effect. Atomistic molecular dynamic simulations corroborate the involvement of this acidic residue in forming a high-Affinity Ca 2+ site atop the channel pore. Furthermore, the reported observations provide clarity for past controversies regarding ASIC channel gating. Our findings enhance understanding of ASIC gating mechanisms and provide structural and energetic insights into this unique calcium-binding site.",
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Identification of a unique Ca 2+ -binding site in rat acid-sensing ion channel 3 . / Zuo, Zhicheng; Smith, Rachel N.; Chen, Zhenglan; Agharkar, Amruta S.; Snell, Heather D.; Huang, Ren-Qi; Liu, Jin; Gonzales, Eric B.

In: Nature Communications, Vol. 9, No. 1, 2082, 01.12.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Zuo, Zhicheng

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AU - Snell, Heather D.

AU - Huang, Ren-Qi

AU - Liu, Jin

AU - Gonzales, Eric B.

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