L-3,3’,5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors


Autoři: Steven X. Moffett aff001;  Eric A. Klein aff001;  Grace Brannigan aff001;  Joseph V. Martin aff001
Působiště autorů: Center for Computational and Integrative Biology, Rutgers University—Camden, Camden, New Jersey, United States of America aff001;  Department of Biology, Rutgers University—Camden, Camden, New Jersey, United States of America aff002;  Department of Physics, Rutgers University—Camden, Camden, New Jersey, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223272

Souhrn

The nicotinic acetylcholine receptor (nAChR) is an excitatory pentameric ligand-gated ion channel (pLGIC), homologous to the inhibitory γ-aminobutyric acid (GABA) type A receptor targeted by pharmaceuticals and endogenous sedatives. Activation of the GABAA receptor by the neurosteroid allopregnanolone can be inhibited competitively by thyroid hormone (L-3,3’,5-triiodothyronine, or T3), but modulation of nAChR by T3 or neurosteroids has not been investigated. Here we show that allopregnanolone inhibits the nAChR from Torpedo californica at micromolar concentrations, as do T3 and the anionic neurosteroid pregnenolone sulfate (PS). We test for the role of protein and ligand charge in mediated receptor inhibition by varying pH in a narrow range around physiological pH. We find that both T3 and PS become less potent with increasing pH, with remarkably similar trends in IC50 when T3 is neutral at pH < 7.3. After deprotonation of T3 (but no additional deprotonation of PS) at pH 7.3, T3 loses potency more slowly with increasing pH than PS. We interpret this result as indicating the negative charge is not required for inhibition but does increase activity. Finally, we show that both T3 and PS affect nAChR channel desensitization, which may implicate a binding site homologous to one that was recently indicated for accelerated desensitization of the GABAA receptor by PS.

Klíčová slova:

Acetylcholine – Nicotinic acetylcholine receptors – Receptor physiology – Sucrose – Sulfates – Thyroid hormones – Xenopus oocytes – Ligand-gated ion channels


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