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TitleGAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 8051, Year 2024
Publish dateSep 14, 2024
AuthorsJiali Wang / Aaron P Owji / Alec Kittredge / Zada Clark / Yu Zhang / Tingting Yang /
PubMed AbstractBestrophin-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 ...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.
External linksNat Commun / PubMed:39277606 / PubMed Central
MethodsEM (single particle)
Resolution2.41 - 2.5 Å
Structure data

45915

9ctq

EMDB-45915, PDB-9ctq:
Best1 + GABA open state
Method: EM (single particle) / Resolution: 2.41 Å

45916

9ctr

EMDB-45916, PDB-9ctr:
Best1 + GABA intermediate state 1
Method: EM (single particle) / Resolution: 2.42 Å

45917

9cts

EMDB-45917, PDB-9cts:
Best1 + GABA intermediate state 2
Method: EM (single particle) / Resolution: 2.45 Å

45918

9ctt

EMDB-45918, PDB-9ctt:
Best1 + GABA closed state
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / calcium-activated chloride channel / GABA type A receptor / GABA-bound anion channel / channel-activator complex

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