{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:14:33Z","timestamp":1790709273347,"version":"4.1.0"},"reference-count":78,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"931","funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-162172"],"award-info":[{"award-number":["PJT-162172"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2024-05445"],"award-info":[{"award-number":["RGPIN-2024-05445"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["KAKENHI JP21H04791"],"award-info":[{"award-number":["KAKENHI JP21H04791"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JP24K21281"],"award-info":[{"award-number":["JP24K21281"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["121038"],"award-info":[{"award-number":["121038"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["0127007"],"award-info":[{"award-number":["0127007"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJFR215T"],"award-info":[{"award-number":["JPMJFR215T"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJMS2023"],"award-info":[{"award-number":["JPMJMS2023"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2026,3,31]]},"abstract":"<jats:p>\n                    Pirenzepine (PZ) and muscarinic toxin 7 (MT7) are muscarinic acetylcholine type 1 receptor (M\n                    <jats:sub>1<\/jats:sub>\n                    R) antagonists that promote neuritogenesis in primary adult rodent dorsal root ganglion (DRG) sensory neurons, in part through \u03b2-arrestin\u2013dependent activation of ERK1\/2. Here, we found that PZ and MT7 exhibited \u03b2-arrestin\u2013biased agonism at M\n                    <jats:sub>1<\/jats:sub>\n                    R. PZ and MT7 recruited \u03b2-arrestin 2 to M\n                    <jats:sub>1<\/jats:sub>\n                    R and increased ERK phosphorylation in both HEK293 cells and DRG neurons in a concentration-dependent manner. Moreover, ERK activation by MT7 occurred only in M\n                    <jats:sub>1<\/jats:sub>\n                    R-positive DRG neurons and did not require G protein signaling or receptor internalization. PZ stimulated M\n                    <jats:sub>1<\/jats:sub>\n                    R phosphorylation at multiple serine and threonine residues. Mutation of Ser\n                    <jats:sup>251<\/jats:sup>\n                    and Thr\n                    <jats:sup>254<\/jats:sup>\n                    in M\n                    <jats:sub>1<\/jats:sub>\n                    R suppressed PZ- and MT7-dependent activation of \u03b2-arrestins and PZ-dependent \u03b2-arrestin binding and ERK activation. The \u03b2-arrestin\u2013biased activities of PZ and MT7 required the activity of casein kinase 2 (CK2) but not that of G\u03b1\n                    <jats:sub>q<\/jats:sub>\n                    or GPCR kinases (GRKs). Pharmacological or siRNA-based inhibition of CK2 blocked PZ-dependent \u03b2-arrestin recruitment, ERK activation, and neurite outgrowth in DRG neurons. These results implicate a GRK- and G protein\u2013independent mechanism for the \u03b2-arrestin\u2013biased agonism and antimuscarinic effects of PZ and MT7.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.ady7187","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T17:58:18Z","timestamp":1774979898000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Antimuscarinic drugs exert \u03b2-arrestin\u2013biased agonism at the muscarinic acetylcholine type 1 receptor to promote DRG neuritogenesis"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5883-3687","authenticated-orcid":true,"given":"Shayan","family":"Amiri","sequence":"first","affiliation":[{"name":"Division of Neurodegenerative and Neurodevelopmental Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada."},{"name":"Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1495-748X","authenticated-orcid":true,"given":"Mohamad-Reza","family":"Aghanoori","sequence":"additional","affiliation":[{"name":"Division of Neurodegenerative and Neurodevelopmental Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada."},{"name":"Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrell R.","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Neurodegenerative and Neurodevelopmental Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. M. Zaved","family":"Waise","sequence":"additional","affiliation":[{"name":"Division of Neurodegenerative and Neurodevelopmental Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Lao","sequence":"additional","affiliation":[{"name":"Manitoba Centre for Proteomics and Systems Biology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0805-4049","authenticated-orcid":true,"given":"Asuka","family":"Inoue","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan."},{"name":"Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 P.","family":"Zahedi","sequence":"additional","affiliation":[{"name":"Manitoba Centre for Proteomics and Systems Biology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada."},{"name":"Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2543-4740","authenticated-orcid":true,"given":"Henry A.","family":"Dunn","sequence":"additional","affiliation":[{"name":"Division of Neurodegenerative and Neurodevelopmental Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada."},{"name":"Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9507-1201","authenticated-orcid":true,"given":"Paul","family":"Fernyhough","sequence":"additional","affiliation":[{"name":"Division of Neurodegenerative and Neurodevelopmental Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada."},{"name":"Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01552.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2013.10.008"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coemr.2020.09.002"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1700331114"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200610018"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3380175"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.229"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0049-3"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(93)90300-R"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.11-10-03218.1991"},{"key":"e_1_3_2_12_2","first-page":"222","article-title":"Rat dorsal root ganglia express m1-m4 muscarinic receptor proteins","volume":"4","author":"Bernardini N.","year":"1999","unstructured":"N. Bernardini, A. I. Levey, G. Augusti-Tocco, Rat dorsal root ganglia express m1-m4 muscarinic receptor proteins. J. Peripher. Nerv. Syst. 4, 222\u2013232 (1999).","journal-title":"J. Peripher. Nerv. Syst."},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchemneu.2007.03.001"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.681726"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.606656"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.536672"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00402"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02588.x"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.44.101802.121622"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.2001.1042"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M011563200"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhv227"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0453-9"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI88321"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.09.020"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2001707"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707936104"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/cn100011e"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806124200"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.74101"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.04.038"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.041604898"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.044750"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax2517"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707662"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2003.12.008"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.01.051"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5247.363"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28152-8"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00567-7"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606267113"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0337-12.2012"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm501173q"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-03-00977.2000"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.150128"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(05)80110-X"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.2174\/1875397300801010070"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1994.tb14779.x"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.108.050773"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703606"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2023.1162049"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.017145"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.712562"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.4c01035"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.261404"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1042\/BC20090171"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-895X(25)11261-3"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm9705115"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1997.337be.x"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.18.12355"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-022-03003-1"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.014"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02661-3"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2024.05.007"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000769"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(02)02043-6"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107848"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2020.09.043"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-009-9155-x"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2013.05.013"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2023.05.005"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.2174\/1871524916666160302103033"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2107389118"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.115.098293"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2018.04.022"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-022-03623-y"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28056-7"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aal3395"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-14-05239.2001"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.ady7187","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T17:58:23Z","timestamp":1774979903000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.ady7187"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":78,"journal-issue":{"issue":"931","published-print":{"date-parts":[[2026,3,31]]}},"alternative-id":["10.1126\/scisignal.ady7187"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.ady7187","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]},"assertion":[{"value":"2025-05-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eady7187"}}