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L-3,3',5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors.
PLoS One 2019; 14(10):e0223272Plos

Abstract

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.

Authors+Show Affiliations

Center for Computational and Integrative Biology, Rutgers University-Camden, Camden, New Jersey, United States of America.Center for Computational and Integrative Biology, Rutgers University-Camden, Camden, New Jersey, United States of America. Department of Biology, Rutgers University-Camden, Camden, New Jersey, United States of America.Center for Computational and Integrative Biology, Rutgers University-Camden, Camden, New Jersey, United States of America. Department of Physics, Rutgers University-Camden, Camden, New Jersey, United States of America.Center for Computational and Integrative Biology, Rutgers University-Camden, Camden, New Jersey, United States of America. Department of Biology, Rutgers University-Camden, Camden, New Jersey, United States of America.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31584962

Citation

Moffett, Steven X., et al. "L-3,3',5-triiodothyronine and Pregnenolone Sulfate Inhibit Torpedo Nicotinic Acetylcholine Receptors." PloS One, vol. 14, no. 10, 2019, pp. e0223272.
Moffett SX, Klein EA, Brannigan G, et al. L-3,3',5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors. PLoS ONE. 2019;14(10):e0223272.
Moffett, S. X., Klein, E. A., Brannigan, G., & Martin, J. V. (2019). L-3,3',5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors. PloS One, 14(10), pp. e0223272. doi:10.1371/journal.pone.0223272.
Moffett SX, et al. L-3,3',5-triiodothyronine and Pregnenolone Sulfate Inhibit Torpedo Nicotinic Acetylcholine Receptors. PLoS ONE. 2019;14(10):e0223272. PubMed PMID: 31584962.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - L-3,3',5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors. AU - Moffett,Steven X, AU - Klein,Eric A, AU - Brannigan,Grace, AU - Martin,Joseph V, Y1 - 2019/10/04/ PY - 2019/03/25/received PY - 2019/09/17/accepted PY - 2019/10/5/entrez PY - 2019/10/5/pubmed PY - 2019/10/5/medline SP - e0223272 EP - e0223272 JF - PloS one JO - PLoS ONE VL - 14 IS - 10 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/31584962/L-3,3',5-triiodothyronine_and_pregnenolone_sulfate_inhibit_Torpedo_nicotinic_acetylcholine_receptors L2 - http://dx.plos.org/10.1371/journal.pone.0223272 DB - PRIME DP - Unbound Medicine ER -