L-3,3',5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors
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 allopregnanolo...
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| description | 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. |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0223272</identifier><identifier>PMID: 31584962</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetylcholine receptors (nicotinic) ; Animals ; Anxiety ; Binding sites ; Biology ; Biology and Life Sciences ; Brain research ; Desensitization ; Dose-Response Relationship, Drug ; GABA ; GABA-A Receptor Antagonists - chemistry ; GABA-A Receptor Antagonists - pharmacology ; Homology ; Hormones ; Inhibitory Concentration 50 ; Ion channels ; Kinetics ; Ligands ; Medicine and Health Sciences ; Menopause ; Molecular Structure ; Nervous system ; Neurosciences ; Neurosteroids ; Nicotinic Antagonists - chemistry ; Nicotinic Antagonists - pharmacology ; Nicotinic receptors ; Oocytes - metabolism ; pH effects ; Phosphorylation ; Physical Sciences ; Pregnanolone ; Pregnenolone ; Pregnenolone - chemistry ; Pregnenolone - pharmacology ; Pregnenolone sulfate ; Progesterone ; Proteins ; Receptors ; Receptors, GABA-A - metabolism ; Receptors, Nicotinic - metabolism ; Research and Analysis Methods ; Rodents ; Sedatives ; Sleep ; Steroids (Drugs) ; Sulfates ; Surface active agents ; Thyroid ; Thyroid gland ; Thyroid hormones ; Torpedo - metabolism ; Triiodothyronine ; Triiodothyronine - chemistry ; Triiodothyronine - pharmacology ; γ-Aminobutyric acid A receptors</subject><ispartof>PloS one, 2019-10, Vol.14 (10), p.e0223272-e0223272</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Moffett et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Moffett et al 2019 Moffett et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-9c701d2d6f061f3ece5505325f65ea2e0788796ba6126cfb74304635cadac9013</citedby><cites>FETCH-LOGICAL-c692t-9c701d2d6f061f3ece5505325f65ea2e0788796ba6126cfb74304635cadac9013</cites><orcidid>0000-0003-3757-3091</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777777/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777777/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31584962$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Hinton, Tina</contributor><creatorcontrib>Moffett, Steven X</creatorcontrib><creatorcontrib>Klein, Eric A</creatorcontrib><creatorcontrib>Brannigan, Grace</creatorcontrib><creatorcontrib>Martin, Joseph V</creatorcontrib><title>L-3,3',5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Acetylcholine receptors (nicotinic)</subject><subject>Animals</subject><subject>Anxiety</subject><subject>Binding sites</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Brain research</subject><subject>Desensitization</subject><subject>Dose-Response Relationship, Drug</subject><subject>GABA</subject><subject>GABA-A Receptor Antagonists - chemistry</subject><subject>GABA-A Receptor Antagonists - pharmacology</subject><subject>Homology</subject><subject>Hormones</subject><subject>Inhibitory Concentration 50</subject><subject>Ion channels</subject><subject>Kinetics</subject><subject>Ligands</subject><subject>Medicine and Health Sciences</subject><subject>Menopause</subject><subject>Molecular Structure</subject><subject>Nervous system</subject><subject>Neurosciences</subject><subject>Neurosteroids</subject><subject>Nicotinic Antagonists - chemistry</subject><subject>Nicotinic Antagonists - pharmacology</subject><subject>Nicotinic receptors</subject><subject>Oocytes - metabolism</subject><subject>pH effects</subject><subject>Phosphorylation</subject><subject>Physical Sciences</subject><subject>Pregnanolone</subject><subject>Pregnenolone</subject><subject>Pregnenolone - chemistry</subject><subject>Pregnenolone - pharmacology</subject><subject>Pregnenolone sulfate</subject><subject>Progesterone</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors, GABA-A - metabolism</subject><subject>Receptors, Nicotinic - metabolism</subject><subject>Research and Analysis Methods</subject><subject>Rodents</subject><subject>Sedatives</subject><subject>Sleep</subject><subject>Steroids (Drugs)</subject><subject>Sulfates</subject><subject>Surface active agents</subject><subject>Thyroid</subject><subject>Thyroid gland</subject><subject>Thyroid hormones</subject><subject>Torpedo - metabolism</subject><subject>Triiodothyronine</subject><subject>Triiodothyronine - 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chemistry</topic><topic>GABA-A Receptor Antagonists - pharmacology</topic><topic>Homology</topic><topic>Hormones</topic><topic>Inhibitory Concentration 50</topic><topic>Ion channels</topic><topic>Kinetics</topic><topic>Ligands</topic><topic>Medicine and Health Sciences</topic><topic>Menopause</topic><topic>Molecular Structure</topic><topic>Nervous system</topic><topic>Neurosciences</topic><topic>Neurosteroids</topic><topic>Nicotinic Antagonists - chemistry</topic><topic>Nicotinic Antagonists - pharmacology</topic><topic>Nicotinic receptors</topic><topic>Oocytes - metabolism</topic><topic>pH effects</topic><topic>Phosphorylation</topic><topic>Physical Sciences</topic><topic>Pregnanolone</topic><topic>Pregnenolone</topic><topic>Pregnenolone - chemistry</topic><topic>Pregnenolone - pharmacology</topic><topic>Pregnenolone sulfate</topic><topic>Progesterone</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Receptors, GABA-A - metabolism</topic><topic>Receptors, Nicotinic - metabolism</topic><topic>Research and Analysis Methods</topic><topic>Rodents</topic><topic>Sedatives</topic><topic>Sleep</topic><topic>Steroids (Drugs)</topic><topic>Sulfates</topic><topic>Surface active agents</topic><topic>Thyroid</topic><topic>Thyroid gland</topic><topic>Thyroid hormones</topic><topic>Torpedo - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moffett, Steven X</au><au>Klein, Eric A</au><au>Brannigan, Grace</au><au>Martin, Joseph V</au><au>Hinton, Tina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>L-3,3',5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-10-04</date><risdate>2019</risdate><volume>14</volume><issue>10</issue><spage>e0223272</spage><epage>e0223272</epage><pages>e0223272-e0223272</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31584962</pmid><doi>10.1371/journal.pone.0223272</doi><tpages>e0223272</tpages><orcidid>https://orcid.org/0000-0003-3757-3091</orcidid><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acetylcholine receptors (nicotinic) Animals Anxiety Binding sites Biology Biology and Life Sciences Brain research Desensitization Dose-Response Relationship, Drug GABA GABA-A Receptor Antagonists - chemistry GABA-A Receptor Antagonists - pharmacology Homology Hormones Inhibitory Concentration 50 Ion channels Kinetics Ligands Medicine and Health Sciences Menopause Molecular Structure Nervous system Neurosciences Neurosteroids Nicotinic Antagonists - chemistry Nicotinic Antagonists - pharmacology Nicotinic receptors Oocytes - metabolism pH effects Phosphorylation Physical Sciences Pregnanolone Pregnenolone Pregnenolone - chemistry Pregnenolone - pharmacology Pregnenolone sulfate Progesterone Proteins Receptors Receptors, GABA-A - metabolism Receptors, Nicotinic - metabolism Research and Analysis Methods Rodents Sedatives Sleep Steroids (Drugs) Sulfates Surface active agents Thyroid Thyroid gland Thyroid hormones Torpedo - metabolism Triiodothyronine Triiodothyronine - chemistry Triiodothyronine - pharmacology γ-Aminobutyric acid A receptors |
| title | L-3,3',5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-02T10%3A01%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=L-3,3',5-triiodothyronine%20and%20pregnenolone%20sulfate%20inhibit%20Torpedo%20nicotinic%20acetylcholine%20receptors&rft.jtitle=PloS%20one&rft.au=Moffett,%20Steven%20X&rft.date=2019-10-04&rft.volume=14&rft.issue=10&rft.spage=e0223272&rft.epage=e0223272&rft.pages=e0223272-e0223272&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0223272&rft_dat=%3Cgale_plos_%3EA601726298%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2300990094&rft_id=info:pmid/31584962&rft_galeid=A601726298&rft_doaj_id=oai_doaj_org_article_434c9e3171b64475a5ef8dc3bc45278b&rfr_iscdi=true |