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Identification of a unique Ca2+-binding site in rat acid-sensing ion channel 3

Author

Listed:
  • Zhicheng Zuo

    (University of North Texas System College of Pharmacy, University of North Texas Health Science Center)

  • Rachel N. Smith

    (University of North Texas Health Science Center)

  • Zhenglan Chen

    (University of North Texas Health Science Center)

  • Amruta S. Agharkar

    (University of North Texas Health Science Center)

  • Heather D. Snell

    (University of North Texas Health Science Center)

  • Renqi Huang

    (University of North Texas Health Science Center)

  • Jin Liu

    (University of North Texas System College of Pharmacy, University of North Texas Health Science Center)

  • Eric B. Gonzales

    (TCU and UNTHSC School of Medicine (Candidate for LCME accreditation))

Abstract

Acid-sensing ion channels (ASICs) evolved to sense changes in extracellular acidity with the divalent cation calcium (Ca2+) as an allosteric modulator and channel blocker. The channel-blocking activity is most apparent in ASIC3, as removing Ca2+ 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 Ca2+ block site. Mutation of this residue to glycine, the equivalent residue in chicken ASIC1, diminished the rASIC3 Ca2+ block effect. Atomistic molecular dynamic simulations corroborate the involvement of this acidic residue in forming a high-affinity Ca2+ 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.

Suggested Citation

  • Zhicheng Zuo & Rachel N. Smith & Zhenglan Chen & Amruta S. Agharkar & Heather D. Snell & Renqi Huang & Jin Liu & Eric B. Gonzales, 2018. "Identification of a unique Ca2+-binding site in rat acid-sensing ion channel 3," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04424-0
    DOI: 10.1038/s41467-018-04424-0
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