{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T05:47:35Z","timestamp":1782884855281,"version":"3.54.5"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T00:00:00Z","timestamp":1582156800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T00:00:00Z","timestamp":1582156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P019366\/1"],"award-info":[{"award-number":["MR\/P019366\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P019366\/1"],"award-info":[{"award-number":["MR\/P019366\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["201529\/Z\/16\/Z"],"award-info":[{"award-number":["201529\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","award":["PPG2017B-005"],"award-info":[{"award-number":["PPG2017B-005"]}],"id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Chem Biol"],"published-print":{"date-parts":[[2020,3,1]]},"DOI":"10.1038\/s41589-019-0453-9","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T11:02:52Z","timestamp":1582196572000},"page":"240-249","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs"],"prefix":"10.1038","volume":"16","author":[{"given":"Sophie J.","family":"Bradley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7179-7721","authenticated-orcid":false,"given":"Colin","family":"Molloy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Valuskova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Dwomoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Scarpa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4668-2863","authenticated-orcid":false,"given":"Lisa","family":"Finlayson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjell A.","family":"Svensson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyassu","family":"Chernet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa N.","family":"Barth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Gherbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Sykes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline A.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajendra","family":"Mistry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8902-2473","authenticated-orcid":false,"given":"Patrick M.","family":"Sexton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Christopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian J.","family":"Mogg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Rosethorne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6796-411X","authenticated-orcid":false,"given":"Shuzo","family":"Sakata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5506-2848","authenticated-orcid":false,"given":"R. A.","family":"John Challiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Broad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1807-3123","authenticated-orcid":false,"given":"Andrew B.","family":"Tobin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,20]]},"reference":[{"key":"453_CR1","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1126\/science.7046051","volume":"217","author":"RT Bartus","year":"1982","unstructured":"Bartus, R. T., Dean, R. L.III., Beer, B. & Lippa, A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408\u2013414 (1982).","journal-title":"Science"},{"key":"453_CR2","doi-asserted-by":"publisher","first-page":"2105","DOI":"10.1016\/S0140-6736(04)16499-4","volume":"363","author":"C Courtney","year":"2004","unstructured":"Courtney, C. et al. Long-term donepezil treatment in 565 patients with Alzheimer\u2019s disease (AD2000): randomised double-blind trial. Lancet 363, 2105\u20132115 (2004).","journal-title":"Lancet"},{"key":"453_CR3","first-page":"45","volume":"127","author":"F Inglis","year":"2002","unstructured":"Inglis, F. The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. Int. J. Clin. Pract 127, 45\u201363 (2002).","journal-title":"Int. J. Clin. Pract"},{"key":"453_CR4","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1172\/JCI87526","volume":"127","author":"SJ Bradley","year":"2017","unstructured":"Bradley, S. J. et al. M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. J. Clin. Invest. 127, 487\u2013499 (2017).","journal-title":"J. Clin. Invest."},{"key":"453_CR5","doi-asserted-by":"publisher","first-page":"8532","DOI":"10.1523\/JNEUROSCI.0337-12.2012","volume":"32","author":"GJ Digby","year":"2012","unstructured":"Digby, G. J. et al. Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. J. Neurosci. 32, 8532\u20138544 (2012).","journal-title":"J. Neurosci."},{"key":"453_CR6","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1038\/npp.2015.189","volume":"41","author":"A Ghoshal","year":"2016","unstructured":"Ghoshal, A. et al. Potentiation of M1 muscarinic receptor reverses plasticity deficits and negative and cognitive symptoms in a schizophrenia mouse model. Neuropsychopharmacology 41, 598\u2013610 (2016).","journal-title":"Neuropsychopharmacology"},{"key":"453_CR7","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1038\/s41386-018-0033-9","volume":"43","author":"SP Moran","year":"2018","unstructured":"Moran, S. P. et al. M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition. Neuropsychopharmacology 43, 1763\u20131771 (2018).","journal-title":"Neuropsychopharmacology"},{"key":"453_CR8","doi-asserted-by":"publisher","first-page":"14271","DOI":"10.1523\/JNEUROSCI.3930-09.2009","volume":"29","author":"JK Shirey","year":"2009","unstructured":"Shirey, J. K. et al. A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J. Neurosci. 29, 14271\u201314286 (2009).","journal-title":"J. Neurosci."},{"key":"453_CR9","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1001\/archneur.1997.00550160091022","volume":"54","author":"NC Bodick","year":"1997","unstructured":"Bodick, N. C. et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch. Neurol. 54, 465\u2013473 (1997).","journal-title":"Arch. Neurol."},{"key":"453_CR10","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1124\/mol.118.111872","volume":"93","author":"SJ Bradley","year":"2018","unstructured":"Bradley, S. J. et al. Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes. Mol. Pharmacol. 93, 645\u2013656 (2018).","journal-title":"Mol. Pharmacol."},{"key":"453_CR11","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1021\/ml100105x","volume":"1","author":"B Budzik","year":"2010","unstructured":"Budzik, B. et al. Novel N-substituted benzimidazolones as potent, selective, CNS-penetrant, and orally active M1 mAChR agonists. ACS Med. Chem. Lett. 1, 244\u2013248 (2010).","journal-title":"ACS Med. Chem. Lett."},{"key":"453_CR12","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1017\/S1461145712000752","volume":"16","author":"PJ Nathan","year":"2013","unstructured":"Nathan, P. J. et al. The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction. Int. J. Neuropsychopharmacol. 16, 721\u2013731 (2013).","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"453_CR13","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrd2760","volume":"8","author":"PJ Conn","year":"2009","unstructured":"Conn, P. J., Christopoulos, A. & Lindsley, C. W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8, 41\u201354 (2009).","journal-title":"Nat. Rev. Drug Discov."},{"key":"453_CR14","doi-asserted-by":"publisher","first-page":"6649","DOI":"10.1021\/acs.jmedchem.7b00597","volume":"60","author":"JE Davoren","year":"2017","unstructured":"Davoren, J. E. et al. Design and synthesis of \u03b3- and \u03b4-lactam M1 positive allosteric modulators (PAMs): convulsion and cholinergic toxicity of an M1-selective PAM with weak agonist activity. J. Med. Chem. 60, 6649\u20136663 (2017).","journal-title":"J. Med. Chem."},{"key":"453_CR15","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1021\/acschemneuro.6b00429","volume":"8","author":"JM Rook","year":"2017","unstructured":"Rook, J. M. et al. Diverse effects on M1 signaling and adverse effect liability within a series of M1 Ago-PAMs. ACS Chem. Neurosci. 8, 866\u2013883 (2017).","journal-title":"ACS Chem. Neurosci."},{"key":"453_CR16","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.nbd.2013.09.013","volume":"61","author":"HH Nickols","year":"2014","unstructured":"Nickols, H. H. & Conn, P. J. Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol. Dis. 61, 55\u201371 (2014).","journal-title":"Neurobiol. Dis."},{"key":"453_CR17","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/nrd.2017.229","volume":"17","author":"JS Smith","year":"2018","unstructured":"Smith, J. S., Lefkowitz, R. J. & Rajagopal, S. Biased signalling: from simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. 17, 243\u2013260 (2018).","journal-title":"Nat. Rev. Drug Discov."},{"key":"453_CR18","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1124\/mol.108.052886","volume":"75","author":"JE Marlo","year":"2009","unstructured":"Marlo, J. E. et al. Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity. Mol. Pharmacol. 75, 577\u2013588 (2009).","journal-title":"Mol. Pharmacol."},{"key":"453_CR19","doi-asserted-by":"publisher","first-page":"5163","DOI":"10.1073\/pnas.0700293104","volume":"104","author":"BN Armbruster","year":"2007","unstructured":"Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S. & Roth, B. L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163\u20135168 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"453_CR20","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.neuron.2016.01.040","volume":"89","author":"BL Roth","year":"2016","unstructured":"Roth, B. L. DREADDs for neuroscientists. Neuron 89, 683\u2013694 (2016).","journal-title":"Neuron"},{"key":"453_CR21","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1021\/acsptsci.8b00012","volume":"1","author":"KJ Thompson","year":"2018","unstructured":"Thompson, K. J. et al. DREADD agonist 21 is an effective agonist for muscarinic-based DREADDs in vitro and in vivo. ACS Pharm. Transl. Sci. 1, 61\u201372 (2018).","journal-title":"ACS Pharm. Transl. Sci."},{"key":"453_CR22","doi-asserted-by":"publisher","first-page":"15312","DOI":"10.1073\/pnas.261583798","volume":"98","author":"DJ Gerber","year":"2001","unstructured":"Gerber, D. J. et al. Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice. Proc. Natl Acad. Sci. USA 98, 15312\u201315317 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"453_CR23","doi-asserted-by":"publisher","first-page":"4524","DOI":"10.1073\/pnas.1521706113","volume":"113","author":"SJ Bradley","year":"2016","unstructured":"Bradley, S. J. et al. Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction. Proc. Natl Acad. Sci. USA 113, 4524\u20134529 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"453_CR24","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.tem.2006.03.008","volume":"17","author":"E Reiter","year":"2006","unstructured":"Reiter, E. & Lefkowitz, R. J. GRKs and \u03b2-arrestins: roles in receptor silencing, trafficking and signaling. Trends Endocrinol. Metab. 17, 159\u2013165 (2006).","journal-title":"Trends Endocrinol. Metab."},{"key":"453_CR25","doi-asserted-by":"publisher","first-page":"8862","DOI":"10.1074\/jbc.M115.681726","volume":"291","author":"AJ Butcher","year":"2016","unstructured":"Butcher, A. J. et al. An antibody biosensor establishes the activation of the M1 muscarinic acetylcholine receptor during learning and memory. J. Biol. Chem. 291, 8862\u20138875 (2016).","journal-title":"J. Biol. Chem."},{"key":"453_CR26","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1124\/mol.66.2.260","volume":"66","author":"D Gautam","year":"2004","unstructured":"Gautam, D. et al. Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice. Mol. Pharmacol. 66, 260\u2013267 (2004).","journal-title":"Mol. Pharmacol."},{"key":"453_CR27","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1124\/jpet.115.226910","volume":"356","author":"A Alt","year":"2016","unstructured":"Alt, A. et al. Evidence for classical cholinergic toxicity associated with selective activation of M1 muscarinic receptors. J. Pharmacol. Exp. Ther. 356, 293\u2013304 (2016).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"453_CR28","doi-asserted-by":"crossref","first-page":"S16","DOI":"10.1097\/00002093-199703000-00004","volume":"11","author":"NC Bodick","year":"1997","unstructured":"Bodick, N. C. et al. The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease. Alzheimer Dis. Assoc. Disord. 11, S16\u2013S22 (1997).","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"453_CR29","doi-asserted-by":"publisher","first-page":"6313","DOI":"10.1021\/acs.jmedchem.6b00544","volume":"59","author":"JE Davoren","year":"2016","unstructured":"Davoren, J. E. et al. Discovery of the potent and selective M1 PAM-agonist N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): evaluation of efficacy and cholinergic side effects. J. Med. Chem. 59, 6313\u20136328 (2016).","journal-title":"J. Med. Chem."},{"key":"453_CR30","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.neuropharm.2018.01.028","volume":"136","author":"CC Felder","year":"2018","unstructured":"Felder, C. C. et al. Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases. Neuropharmacology 136, 449\u2013458 (2018).","journal-title":"Neuropharmacology"},{"key":"453_CR31","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1111\/j.1528-1157.1996.tb00541.x","volume":"37","author":"EA Cavalheiro","year":"1996","unstructured":"Cavalheiro, E. A., Santos, N. F. & Priel, M. R. The pilocarpine model of epilepsy in mice. Epilepsia 37, 1015\u20131019 (1996).","journal-title":"Epilepsia"},{"key":"453_CR32","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.jneumeth.2015.03.009","volume":"260","author":"M Levesque","year":"2016","unstructured":"Levesque, M., Avoli, M. & Bernard, C. Animal models of temporal lobe epilepsy following systemic chemoconvulsant administration. J. Neurosci. Methods 260, 45\u201352 (2016).","journal-title":"J. Neurosci. Methods"},{"key":"453_CR33","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/0166-4328(83)90136-5","volume":"9","author":"WA Turski","year":"1983","unstructured":"Turski, W. A. et al. Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study. Behav. Brain Res. 9, 315\u2013335 (1983).","journal-title":"Behav. Brain Res."},{"key":"453_CR34","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1124\/jpet.117.246454","volume":"365","author":"AJ Mogg","year":"2018","unstructured":"Mogg, A. J. et al. In vitro pharmacological characterization and in vivo validation of LSN3172176 a novel M1 selective muscarinic receptor agonist tracer molecule for positron emission tomography (PET). J. Pharmacol. Exp. Ther. 365, 602\u2013613 (2018).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"453_CR35","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1021\/acschemneuro.7b00001","volume":"8","author":"AM Bender","year":"2017","unstructured":"Bender, A. M., Jones, C. K. & Lindsley, C. W. Classics in chemical neuroscience: xanomeline. ACS Chem. Neurosci. 8, 435\u2013443 (2017).","journal-title":"ACS Chem. Neurosci."},{"key":"453_CR36","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1124\/mol.115.101949","volume":"89","author":"R Prihandoko","year":"2016","unstructured":"Prihandoko, R. et al. Distinct phosphorylation clusters determine the signaling outcome of free fatty acid receptor 4\/G protein-coupled receptor 120. Mol. Pharmacol. 89, 505\u2013520 (2016).","journal-title":"Mol. Pharmacol."},{"key":"453_CR37","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/j.pharmthera.2005.09.008","volume":"110","author":"VV Gurevich","year":"2006","unstructured":"Gurevich, V. V. & Gurevich, E. V. The structural basis of arrestin-mediated regulation of G-protein-coupled receptors. Pharmacol. Ther. 110, 465\u2013502 (2006).","journal-title":"Pharmacol. Ther."},{"key":"453_CR38","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/nature12120","volume":"497","author":"AK Shukla","year":"2013","unstructured":"Shukla, A. K. et al. Structure of active \u03b2-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497, 137\u2013141 (2013).","journal-title":"Nature"},{"key":"453_CR39","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.cell.2017.07.002","volume":"170","author":"XE Zhou","year":"2017","unstructured":"Zhou, X. E. et al. Identification of phosphorylation codes for arrestin recruitment by G protein-coupled receptors. Cell 170, 457\u2013469 (2017).","journal-title":"Cell"},{"key":"453_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09204-y","volume":"10","author":"D Mayer","year":"2019","unstructured":"Mayer, D. et al. Distinct G protein-coupled receptor phosphorylation motifs modulate arrestin affinity and activation and global conformation. Nat. Commun. 10, 1261 (2019).","journal-title":"Nat. Commun."},{"key":"453_CR41","doi-asserted-by":"publisher","first-page":"3834","DOI":"10.1073\/pnas.1722336115","volume":"115","author":"DP Staus","year":"2018","unstructured":"Staus, D. P. et al. Sortase ligation enables homogeneous GPCR phosphorylation to reveal diversity in \u03b2-arrestin coupling. Proc. Natl Acad. Sci. USA 115, 3834\u20133839 (2018).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"453_CR42","doi-asserted-by":"publisher","first-page":"11506","DOI":"10.1074\/jbc.M110.154526","volume":"286","author":"AJ Butcher","year":"2011","unstructured":"Butcher, A. J. et al. Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code. J. Biol. Chem. 286, 11506\u201311518 (2011).","journal-title":"J. Biol. Chem."},{"key":"453_CR43","doi-asserted-by":"publisher","first-page":"ra51","DOI":"10.1126\/scisignal.2001707","volume":"4","author":"KN Nobles","year":"2011","unstructured":"Nobles, K. N. et al. Distinct phosphorylation sites on the \u03b22-adrenergic receptor establish a barcode that encodes differential functions of \u03b2-arrestin. Sci. Signal. 4, ra51 (2011).","journal-title":"Sci. Signal."},{"key":"453_CR44","doi-asserted-by":"publisher","first-page":"21181","DOI":"10.1073\/pnas.1011651107","volume":"107","author":"KC Kong","year":"2010","unstructured":"Kong, K. C. et al. M3-muscarinic receptor promotes insulin release via receptor phosphorylation\/arrestin-dependent activation of protein kinase D1. Proc. Natl Acad. Sci. USA 107, 21181\u201321186 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"453_CR45","doi-asserted-by":"publisher","first-page":"9440","DOI":"10.1073\/pnas.0914801107","volume":"107","author":"B Poulin","year":"2010","unstructured":"Poulin, B. et al. The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation\/arrestin-dependent manner. Proc. Natl Acad. Sci. USA 107, 9440\u20139445 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"453_CR46","doi-asserted-by":"publisher","first-page":"6366","DOI":"10.1002\/anie.201301924","volume":"52","author":"RJ Lefkowitz","year":"2013","unstructured":"Lefkowitz, R. J. A brief history of G-protein coupled receptors (Nobel Lecture). Angew. Chem. 52, 6366\u20136378 (2013).","journal-title":"Angew. Chem."},{"key":"453_CR47","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.tips.2004.06.006","volume":"25","author":"RJ Lefkowitz","year":"2004","unstructured":"Lefkowitz, R. J. Historical review: a brief history and personal retrospective of seven-transmembrane receptors. Trends Pharmacol. Sci. 25, 413\u2013422 (2004).","journal-title":"Trends Pharmacol. Sci."},{"key":"453_CR48","doi-asserted-by":"publisher","first-page":"5239","DOI":"10.1523\/JNEUROSCI.21-14-05239.2001","volume":"21","author":"T Miyakawa","year":"2001","unstructured":"Miyakawa, T., Yamada, M., Duttaroy, A. & Wess, J. Hyperactivity and intact hippocampus-dependent learning in mice lacking the M1 muscarinic acetylcholine receptor. J. Neurosci. 21, 5239\u20135250 (2001).","journal-title":"J. Neurosci."},{"key":"453_CR49","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1124\/jpet.117.243774","volume":"364","author":"E Kurimoto","year":"2018","unstructured":"Kurimoto, E. et al. An approach to discovering novel muscarinic M1 receptor positive allosteric modulators with potent cognitive improvement and minimized gastrointestinal dysfunction. J. Pharmacol. Exp. Ther. 364, 28\u201337 (2018).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"453_CR50","doi-asserted-by":"publisher","first-page":"2274","DOI":"10.1021\/acschemneuro.8b00131","volume":"9","author":"JM Rook","year":"2018","unstructured":"Rook, J. M. et al. A novel M1 PAM VU0486846 exerts efficacy in cognition models without displaying agonist activity or cholinergic toxicity. ACS Chem. Neurosci. 9, 2274\u20132285 (2018).","journal-title":"ACS Chem. Neurosci."},{"key":"453_CR51","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/S0006-291X(88)80304-8","volume":"157","author":"RA Challiss","year":"1988","unstructured":"Challiss, R. A., Batty, I. H. & Nahorski, S. R. Mass measurements of inositol(1,4,5)trisphosphate in rat cerebral cortex slices using a radioreceptor assay: effects of neurotransmitters and depolarization. Biochem. Biophys. Res. Commun. 157, 684\u2013691 (1988).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"453_CR52","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1080\/07420520600827111","volume":"23","author":"M Arraj","year":"2006","unstructured":"Arraj, M. & Lemmer, B. Circadian rhythms in heart rate, motility, and body temperature of wild-type C57 and eNOS knock-out mice under light-dark, free-run, and after time zone transition. Chronobiol. Int. 23, 795\u2013812 (2006).","journal-title":"Chronobiol. Int"},{"key":"453_CR53","doi-asserted-by":"publisher","first-page":"29","DOI":"10.3389\/fnagi.2019.00029","volume":"11","author":"D Lyngholm","year":"2019","unstructured":"Lyngholm, D. & Sakata, S. Cre-dependent optogenetic transgenic mice without early age-related hearing loss. Front. Aging Neurosci. 11, 29 (2019).","journal-title":"Front. Aging Neurosci."},{"key":"453_CR54","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1124\/mol.113.088880","volume":"85","author":"ET van der Westhuizen","year":"2014","unstructured":"van der Westhuizen, E. T., Breton, B., Christopoulos, A. & Bouvier, M. Quantification of ligand bias for clinically relevant \u03b22-adrenergic receptor ligands: implications for drug taxonomy. Mol. Pharmacol. 85, 492\u2013509 (2014).","journal-title":"Mol. Pharmacol."}],"container-title":["Nature Chemical Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41589-019-0453-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41589-019-0453-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41589-019-0453-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T11:02:55Z","timestamp":1761908575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41589-019-0453-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,20]]},"references-count":54,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,3,1]]}},"alternative-id":["453"],"URL":"https:\/\/doi.org\/10.1038\/s41589-019-0453-9","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.737402762.793571544","asserted-by":"object"}]},"ISSN":["1552-4450","1552-4469"],"issn-type":[{"value":"1552-4450","type":"print"},{"value":"1552-4469","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,20]]},"assertion":[{"value":"12 June 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}