Isoform-Specific Biased Agonism of Histamine H3 Receptor Agonists.
Identifieur interne : 000916 ( PubMed/Checkpoint ); précédent : 000915; suivant : 000917Isoform-Specific Biased Agonism of Histamine H3 Receptor Agonists.
Auteurs : Darren M. Riddy ; Anna E. Cook ; Natalie A. Diepenhorst ; Sanja Bosnyak ; Ryan Brady ; Clotilde Mannoury La Cour ; Elisabeth Mocaer ; Roger J. Summers ; William N. Charman ; Patrick M. Sexton ; Arthur Christopoulos ; Christopher J. Langmead [États-Unis]Source :
- Molecular pharmacology [ 1521-0111 ] ; 2017.
Descripteurs français
- KwdFr :
- AMP cyclique (métabolisme), Agonistes histaminergiques (), Agonistes histaminergiques (pharmacologie), Analyse en composantes principales, Animaux, Cellules CHO, Cricetinae, Cricetulus, Dosage biologique, Délétion de séquence, Humains, Isoformes de protéines (métabolisme), Récepteur histaminergique H3 (métabolisme).
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Histamine Agonists.
- chemical , metabolism : Cyclic AMP, Protein Isoforms, Receptors, Histamine H3.
- chemical , pharmacology : Histamine Agonists.
- Animals, Biological Assay, CHO Cells, Cricetinae, Cricetulus, Humans, Principal Component Analysis, Sequence Deletion.
Abstract
The human histamine H3 receptor (hH3R) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the H3R; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hH3R splice variants (hH3R445 and hH3R365) across seven signaling endpoints. Both isoforms engender biased signaling, notably for 4-[3-(benzyloxy)propyl]-1H-imidazole (proxyfan) [e.g., strong bias toward phosphorylation of glycogen synthase kinase 3β (GSK3β) via the full-length receptor] and its congener 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether (iodoproxyfan), which are strongly consistent with the former's designation as a "protean" agonist. The 80 amino acid IL3 deleted isoform hH3R365 is more permissive in its signaling than hH3R445: 2-(1H-imidazol-5-yl)ethyl imidothiocarbamate (imetit), proxyfan, and iodoproxyfan were all markedly biased away from calcium signaling, and principal component analysis of the full data set revealed divergent profiles for all five agonists. However, most interesting was the identification of differential biased signaling between the two isoforms. Strikingly, hH3R365 was completely unable to stimulate GSK3β phosphorylation, an endpoint robustly activated by the full-length receptor. To the best of our knowledge, this is the first quantitative example of differential biased signaling via isoforms of the same G protein-coupled receptor that are simultaneously expressed in vivo and gives rise to the possibility of selective pharmacological targeting of individual receptor splice variants.
DOI: 10.1124/mol.116.106153
PubMed: 27864425
Affiliations:
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Cook</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Diepenhorst, Natalie A" sort="Diepenhorst, Natalie A" uniqKey="Diepenhorst N" first="Natalie A" last="Diepenhorst">Natalie A. Diepenhorst</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Bosnyak, Sanja" sort="Bosnyak, Sanja" uniqKey="Bosnyak S" first="Sanja" last="Bosnyak">Sanja Bosnyak</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Brady, Ryan" sort="Brady, Ryan" uniqKey="Brady R" first="Ryan" last="Brady">Ryan Brady</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Mannoury La Cour, Clotilde" sort="Mannoury La Cour, Clotilde" uniqKey="Mannoury La Cour C" first="Clotilde" last="Mannoury La Cour">Clotilde Mannoury La Cour</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Mocaer, Elisabeth" sort="Mocaer, Elisabeth" uniqKey="Mocaer E" first="Elisabeth" last="Mocaer">Elisabeth Mocaer</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Summers, Roger J" sort="Summers, Roger J" uniqKey="Summers R" first="Roger J" last="Summers">Roger J. Summers</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Charman, William N" sort="Charman, William N" uniqKey="Charman W" first="William N" last="Charman">William N. Charman</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Sexton, Patrick M" sort="Sexton, Patrick M" uniqKey="Sexton P" first="Patrick M" last="Sexton">Patrick M. Sexton</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Christopoulos, Arthur" sort="Christopoulos, Arthur" uniqKey="Christopoulos A" first="Arthur" last="Christopoulos">Arthur Christopoulos</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Langmead, Christopher J" sort="Langmead, Christopher J" uniqKey="Langmead C" first="Christopher J" last="Langmead">Christopher J. Langmead</name><affiliation wicri:level="1"><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.) chris.langmead@monash.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:27864425</idno><idno type="pmid">27864425</idno><idno type="doi">10.1124/mol.116.106153</idno><idno type="wicri:Area/PubMed/Corpus">001166</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001166</idno><idno type="wicri:Area/PubMed/Curation">001163</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001163</idno><idno type="wicri:Area/PubMed/Checkpoint">001163</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001163</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Isoform-Specific Biased Agonism of Histamine H3 Receptor Agonists.</title><author><name sortKey="Riddy, Darren M" sort="Riddy, Darren M" uniqKey="Riddy D" first="Darren M" last="Riddy">Darren M. Riddy</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Cook, Anna E" sort="Cook, Anna E" uniqKey="Cook A" first="Anna E" last="Cook">Anna E. Cook</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Diepenhorst, Natalie A" sort="Diepenhorst, Natalie A" uniqKey="Diepenhorst N" first="Natalie A" last="Diepenhorst">Natalie A. Diepenhorst</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Bosnyak, Sanja" sort="Bosnyak, Sanja" uniqKey="Bosnyak S" first="Sanja" last="Bosnyak">Sanja Bosnyak</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Brady, Ryan" sort="Brady, Ryan" uniqKey="Brady R" first="Ryan" last="Brady">Ryan Brady</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Mannoury La Cour, Clotilde" sort="Mannoury La Cour, Clotilde" uniqKey="Mannoury La Cour C" first="Clotilde" last="Mannoury La Cour">Clotilde Mannoury La Cour</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Mocaer, Elisabeth" sort="Mocaer, Elisabeth" uniqKey="Mocaer E" first="Elisabeth" last="Mocaer">Elisabeth Mocaer</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Summers, Roger J" sort="Summers, Roger J" uniqKey="Summers R" first="Roger J" last="Summers">Roger J. Summers</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Charman, William N" sort="Charman, William N" uniqKey="Charman W" first="William N" last="Charman">William N. Charman</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Sexton, Patrick M" sort="Sexton, Patrick M" uniqKey="Sexton P" first="Patrick M" last="Sexton">Patrick M. Sexton</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Christopoulos, Arthur" sort="Christopoulos, Arthur" uniqKey="Christopoulos A" first="Arthur" last="Christopoulos">Arthur Christopoulos</name><affiliation><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</nlm:affiliation><wicri:noCountry code="subField">E.M.).</wicri:noCountry></affiliation></author><author><name sortKey="Langmead, Christopher J" sort="Langmead, Christopher J" uniqKey="Langmead C" first="Christopher J" last="Langmead">Christopher J. Langmead</name><affiliation wicri:level="1"><nlm:affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.) chris.langmead@monash.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><series><title level="j">Molecular pharmacology</title><idno type="eISSN">1521-0111</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Biological Assay</term><term>CHO Cells</term><term>Cricetinae</term><term>Cricetulus</term><term>Cyclic AMP (metabolism)</term><term>Histamine Agonists (chemistry)</term><term>Histamine Agonists (pharmacology)</term><term>Humans</term><term>Principal Component Analysis</term><term>Protein Isoforms (metabolism)</term><term>Receptors, Histamine H3 (metabolism)</term><term>Sequence Deletion</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>AMP cyclique (métabolisme)</term><term>Agonistes histaminergiques ()</term><term>Agonistes histaminergiques (pharmacologie)</term><term>Analyse en composantes principales</term><term>Animaux</term><term>Cellules CHO</term><term>Cricetinae</term><term>Cricetulus</term><term>Dosage biologique</term><term>Délétion de séquence</term><term>Humains</term><term>Isoformes de protéines (métabolisme)</term><term>Récepteur histaminergique H3 (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Histamine Agonists</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cyclic AMP</term><term>Protein Isoforms</term><term>Receptors, Histamine H3</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Histamine Agonists</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>AMP cyclique</term><term>Isoformes de protéines</term><term>Récepteur histaminergique H3</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agonistes histaminergiques</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Biological Assay</term><term>CHO Cells</term><term>Cricetinae</term><term>Cricetulus</term><term>Humans</term><term>Principal Component Analysis</term><term>Sequence Deletion</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Agonistes histaminergiques</term><term>Analyse en composantes principales</term><term>Animaux</term><term>Cellules CHO</term><term>Cricetinae</term><term>Cricetulus</term><term>Dosage biologique</term><term>Délétion de séquence</term><term>Humains</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The human histamine H3 receptor (hH3R) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the H3R; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hH3R splice variants (hH3R445 and hH3R365) across seven signaling endpoints. Both isoforms engender biased signaling, notably for 4-[3-(benzyloxy)propyl]-1H-imidazole (proxyfan) [e.g., strong bias toward phosphorylation of glycogen synthase kinase 3β (GSK3β) via the full-length receptor] and its congener 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether (iodoproxyfan), which are strongly consistent with the former's designation as a "protean" agonist. The 80 amino acid IL3 deleted isoform hH3R365 is more permissive in its signaling than hH3R445: 2-(1H-imidazol-5-yl)ethyl imidothiocarbamate (imetit), proxyfan, and iodoproxyfan were all markedly biased away from calcium signaling, and principal component analysis of the full data set revealed divergent profiles for all five agonists. However, most interesting was the identification of differential biased signaling between the two isoforms. Strikingly, hH3R365 was completely unable to stimulate GSK3β phosphorylation, an endpoint robustly activated by the full-length receptor. To the best of our knowledge, this is the first quantitative example of differential biased signaling via isoforms of the same G protein-coupled receptor that are simultaneously expressed in vivo and gives rise to the possibility of selective pharmacological targeting of individual receptor splice variants.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27864425</PMID><DateCreated><Year>2016</Year><Month>11</Month><Day>19</Day></DateCreated><DateCompleted><Year>2017</Year><Month>05</Month><Day>09</Day></DateCompleted><DateRevised><Year>2017</Year><Month>05</Month><Day>09</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1521-0111</ISSN><JournalIssue CitedMedium="Internet"><Volume>91</Volume><Issue>2</Issue><PubDate><Year>2017</Year><Month>Feb</Month></PubDate></JournalIssue><Title>Molecular pharmacology</Title><ISOAbbreviation>Mol. Pharmacol.</ISOAbbreviation></Journal><ArticleTitle>Isoform-Specific Biased Agonism of Histamine H3 Receptor Agonists.</ArticleTitle><Pagination><MedlinePgn>87-99</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1124/mol.116.106153</ELocationID><Abstract><AbstractText>The human histamine H3 receptor (hH3R) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the H3R; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hH3R splice variants (hH3R445 and hH3R365) across seven signaling endpoints. Both isoforms engender biased signaling, notably for 4-[3-(benzyloxy)propyl]-1H-imidazole (proxyfan) [e.g., strong bias toward phosphorylation of glycogen synthase kinase 3β (GSK3β) via the full-length receptor] and its congener 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether (iodoproxyfan), which are strongly consistent with the former's designation as a "protean" agonist. The 80 amino acid IL3 deleted isoform hH3R365 is more permissive in its signaling than hH3R445: 2-(1H-imidazol-5-yl)ethyl imidothiocarbamate (imetit), proxyfan, and iodoproxyfan were all markedly biased away from calcium signaling, and principal component analysis of the full data set revealed divergent profiles for all five agonists. However, most interesting was the identification of differential biased signaling between the two isoforms. Strikingly, hH3R365 was completely unable to stimulate GSK3β phosphorylation, an endpoint robustly activated by the full-length receptor. To the best of our knowledge, this is the first quantitative example of differential biased signaling via isoforms of the same G protein-coupled receptor that are simultaneously expressed in vivo and gives rise to the possibility of selective pharmacological targeting of individual receptor splice variants.</AbstractText><CopyrightInformation>Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Riddy</LastName><ForeName>Darren M</ForeName><Initials>DM</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cook</LastName><ForeName>Anna E</ForeName><Initials>AE</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Diepenhorst</LastName><ForeName>Natalie A</ForeName><Initials>NA</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bosnyak</LastName><ForeName>Sanja</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brady</LastName><ForeName>Ryan</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mannoury la Cour</LastName><ForeName>Clotilde</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mocaer</LastName><ForeName>Elisabeth</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Summers</LastName><ForeName>Roger J</ForeName><Initials>RJ</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Charman</LastName><ForeName>William N</ForeName><Initials>WN</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sexton</LastName><ForeName>Patrick M</ForeName><Initials>PM</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Christopoulos</LastName><ForeName>Arthur</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.).</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Langmead</LastName><ForeName>Christopher J</ForeName><Initials>CJ</Initials><AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.) chris.langmead@monash.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>11</Month><Day>18</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mol Pharmacol</MedlineTA><NlmUniqueID>0035623</NlmUniqueID><ISSNLinking>0026-895X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D017442">Histamine Agonists</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D020033">Protein Isoforms</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018100">Receptors, Histamine H3</NameOfSubstance></Chemical><Chemical><RegistryNumber>E0399OZS9N</RegistryNumber><NameOfSubstance UI="D000242">Cyclic AMP</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="ErratumIn"><RefSource>Mol Pharmacol. 2017 Mar;91(3):263</RefSource><PMID Version="1">28137965</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001681" MajorTopicYN="N">Biological Assay</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016466" MajorTopicYN="N">CHO Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006224" MajorTopicYN="N">Cricetinae</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003412" MajorTopicYN="N">Cricetulus</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000242" MajorTopicYN="N">Cyclic AMP</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017442" MajorTopicYN="N">Histamine Agonists</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D025341" MajorTopicYN="N">Principal Component Analysis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020033" MajorTopicYN="N">Protein Isoforms</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018100" MajorTopicYN="N">Receptors, Histamine H3</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017384" MajorTopicYN="N">Sequence Deletion</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>07</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>11</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>11</Month><Day>20</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>5</Month><Day>10</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>11</Month><Day>20</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27864425</ArticleId><ArticleId IdType="pii">mol.116.106153</ArticleId><ArticleId IdType="doi">10.1124/mol.116.106153</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Bosnyak, Sanja" sort="Bosnyak, Sanja" uniqKey="Bosnyak S" first="Sanja" last="Bosnyak">Sanja Bosnyak</name><name sortKey="Brady, Ryan" sort="Brady, Ryan" uniqKey="Brady R" first="Ryan" last="Brady">Ryan Brady</name><name sortKey="Charman, William N" sort="Charman, William N" uniqKey="Charman W" first="William N" last="Charman">William N. Charman</name><name sortKey="Christopoulos, Arthur" sort="Christopoulos, Arthur" uniqKey="Christopoulos A" first="Arthur" last="Christopoulos">Arthur Christopoulos</name><name sortKey="Cook, Anna E" sort="Cook, Anna E" uniqKey="Cook A" first="Anna E" last="Cook">Anna E. Cook</name><name sortKey="Diepenhorst, Natalie A" sort="Diepenhorst, Natalie A" uniqKey="Diepenhorst N" first="Natalie A" last="Diepenhorst">Natalie A. Diepenhorst</name><name sortKey="Mannoury La Cour, Clotilde" sort="Mannoury La Cour, Clotilde" uniqKey="Mannoury La Cour C" first="Clotilde" last="Mannoury La Cour">Clotilde Mannoury La Cour</name><name sortKey="Mocaer, Elisabeth" sort="Mocaer, Elisabeth" uniqKey="Mocaer E" first="Elisabeth" last="Mocaer">Elisabeth Mocaer</name><name sortKey="Riddy, Darren M" sort="Riddy, Darren M" uniqKey="Riddy D" first="Darren M" last="Riddy">Darren M. Riddy</name><name sortKey="Sexton, Patrick M" sort="Sexton, Patrick M" uniqKey="Sexton P" first="Patrick M" last="Sexton">Patrick M. Sexton</name><name sortKey="Summers, Roger J" sort="Summers, Roger J" uniqKey="Summers R" first="Roger J" last="Summers">Roger J. Summers</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Langmead, Christopher J" sort="Langmead, Christopher J" uniqKey="Langmead C" first="Christopher J" last="Langmead">Christopher J. Langmead</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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