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GAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel

Author

Listed:
  • Jiali Wang

    (Columbia University)

  • Aaron P. Owji

    (Columbia University)

  • Alec Kittredge

    (Columbia University)

  • Zada Clark

    (Columbia University)

  • Yu Zhang

    (Columbia University)

  • Tingting Yang

    (Columbia University)

Abstract

Bestrophin-1 (Best1) is an anion channel genetically linked to vision-threatening retinal degenerative channelopathies. Here, we identify interactions between Best1 and both isoforms of glutamic acid decarboxylases (GAD65 and GAD67), elucidate the distinctive influences of GAD65 and GAD67 on Best1’s permeability to various anions/neurotransmitters, discover the functionality of Best1 as a γ-Aminobutyric acid (GABA) type A receptor, and solve the structure of GABA-bound Best1. GAD65 and GAD67 both promote Best1-mediated Cl− currents, but only GAD65 drastically enhances the permeability of Best1 to glutamate and GABA, for which GAD67 has no effect. GABA binds to Best1 on an extracellular site and stimulates Best1-mediated Cl− currents at the nano-molar concentration level. The physiological role of GAD65 as a cell type-specific binding partner and facilitator of Best1 is demonstrated in retinal pigment epithelial cells. Together, our results reveal critical regulators of Best1 and inform a network of membrane transport metabolons formed between bestrophin channels and glutamate metabolic enzymes.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52039-5
    DOI: 10.1038/s41467-024-52039-5
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    References listed on IDEAS

    as
    1. Yu Zhang & Alec Kittredge & Nancy Ward & Changyi Ji & Shoudeng Chen & Tingting Yang, 2018. "ATP activates bestrophin ion channels through direct interaction," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    2. Aaron P. Owji & Jiali Wang & Alec Kittredge & Zada Clark & Yu Zhang & Wayne A. Hendrickson & Tingting Yang, 2022. "Structures and gating mechanisms of human bestrophin anion channels," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Veronica Kane Dickson & Leanne Pedi & Stephen B. Long, 2014. "Structure and insights into the function of a Ca2+-activated Cl− channel," Nature, Nature, vol. 516(7530), pages 213-218, December.
    4. 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.
    Full references (including those not matched with items on IDEAS)

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