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Bestrophin-2 and glutamine synthetase form a complex for glutamate release

Author

Listed:
  • Aaron P. Owji

    (Columbia University
    Columbia University)

  • Kuai Yu

    (Emory University, School of Medicine)

  • Alec Kittredge

    (Columbia University
    Columbia University)

  • Jiali Wang

    (Columbia University)

  • Yu Zhang

    (Columbia University)

  • Tingting Yang

    (Columbia University)

Abstract

Bestrophin-2 (BEST2) is a member of the bestrophin family of calcium-activated anion channels that has a critical role in ocular physiology1–4. Here we uncover a directional permeability of BEST2 to glutamate that heavily favours glutamate exit, identify glutamine synthetase (GS) as a binding partner of BEST2 in the ciliary body of the eye, and solve the structure of the BEST2–GS complex. BEST2 reduces cytosolic GS activity by tethering GS to the cell membrane. GS extends the ion conducting pathway of BEST2 through its central cavity and inhibits BEST2 channel function in the absence of intracellular glutamate, but sensitizes BEST2 to intracellular glutamate, which promotes the opening of BEST2 and thus relieves the inhibitory effect of GS. We demonstrate the physiological role of BEST2 in conducting chloride and glutamate and the influence of GS in non-pigmented ciliary epithelial cells. Together, our results reveal a novel mechanism of glutamate release through BEST2–GS.

Suggested Citation

  • Aaron P. Owji & Kuai Yu & Alec Kittredge & Jiali Wang & Yu Zhang & Tingting Yang, 2022. "Bestrophin-2 and glutamine synthetase form a complex for glutamate release," Nature, Nature, vol. 611(7934), pages 180-187, November.
    • Handle: RePEc:nat:nature:v:611:y:2022:i:7934:d:10.1038_s41586-022-05373-x
    DOI: 10.1038/s41586-022-05373-x
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    Cited by:

    1. Jiali Wang & Aaron P. Owji & Alec Kittredge & Zada Clark & Yu Zhang & Tingting Yang, 2024. "GAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Jing Wang & Xinyang Zhao & Yucheng Tao & Xiuxiu Wang & Li Yan & Kuang Yu & Yi Hsu & Yuncong Chen & Jing Zhao & Yong Huang & Wei Wei, 2024. "Biocompatible aggregation-induced emission active polyphosphate-manganese nanosheets with glutamine synthetase-like activity in excitotoxic nerve cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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