Membrane cholesterol regulates inhibition and substrate transport by the glycine transporter, GlyT2.
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
Apr 2023
Apr 2023
Historique:
received:
04
09
2022
revised:
10
01
2023
accepted:
11
01
2023
entrez:
23
1
2023
pubmed:
24
1
2023
medline:
26
1
2023
Statut:
epublish
Résumé
Membrane cholesterol binds to and modulates the function of various SLC6 neurotransmitter transporters, including stabilizing the outward-facing conformation of the dopamine and serotonin transporters. Here, we investigate how cholesterol binds to GlyT2 (SLC6A5), modulates glycine transport rate, and influences bioactive lipid inhibition of GlyT2. Bioactive lipid inhibitors are analgesics that bind to an allosteric site accessible from the extracellular solution when GlyT2 adopts an outward-facing conformation. Using molecular dynamics simulations, mutagenesis, and cholesterol depletion experiments, we show that bioactive lipid inhibition of glycine transport is modulated by the recruitment of membrane cholesterol to a binding site formed by transmembrane helices 1, 5, and 7. Recruitment involves cholesterol flipping from its membrane orientation, and insertion of the 3' hydroxyl group into the cholesterol binding cavity, close to the allosteric site. The synergy between cholesterol and allosteric inhibitors provides a novel mechanism of inhibition and a potential avenue for the development of potent GlyT2 inhibitors as alternative therapeutics for the treatment of neuropathic pain and therapeutics that target other SLC6 transporters.
Identifiants
pubmed: 36690444
pii: 6/4/e202201708
doi: 10.26508/lsa.202201708
pmc: PMC9873984
pii:
doi:
Substances chimiques
Glycine Plasma Membrane Transport Proteins
0
Glycine
TE7660XO1C
Cholesterol
97C5T2UQ7J
Lipids
0
Banques de données
PDB
['6DZZ', '4M48']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 Frangos et al.
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