Ellul-Micallef, R. History of Bronchial Asthma (Lippincott Raven, 1997).

Moulton, B. C. & Fryer, A. D. Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD. Br. J. Pharmacol. 163, 44–52 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Singh, A., Dikshit, R. & Chaturvedi, P. Betel nut use: the South Asian story. Subst. Use Misuse 55, 1545–1551 (2020).

Article  PubMed  Google Scholar 

Sullivan, R. J., Allen, J. S., Otto, C., Tiobech, J. & Nero, K. Effects of chewing betel nut (Areca catechu) on the symptoms of people with schizophrenia in Palau, Micronesia. Br. J. Psychiatry 177, 174–178 (2000).

Article  CAS  PubMed  Google Scholar 

Feldberg, W. & Gaddum, J. H. The chemical transmitter at synapses in a sympathetic ganglion. J. Physiol. 81, 305–319 (1934).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lopez-Munoz, F. & Alamo, C. Historical evolution of the neurotransmission concept. J. Neural Transm. 116, 515–533 (2009).

Article  CAS  PubMed  Google Scholar 

Felder, C. C. et al. Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases. Neuropharmacology 136, 449–458 (2018).

Article  CAS  PubMed  Google Scholar 

Bender, A. M., Jones, C. K. & Lindsley, C. W. Classics in chemical neuroscience: xanomeline. ACS Chem. Neurosci. 8, 435–443 (2017).

Article  CAS  PubMed  Google Scholar 

Budzik, B. et al. Novel N-substituted benzimidazolones as potent, selective, CNS-penetrant, and orally active M1 mAChR agonists. ACS Med. Chem. Lett. 1, 244–248 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Viberg, A., Martino, G., Lessard, E. & Laird, J. M. Evaluation of an innovative population pharmacokinetic-based design for behavioral pharmacodynamic endpoints. AAPS J. 14, 657–663 (2012).

Article  PubMed  PubMed Central  Google Scholar 

Okada, H. et al. Alterations in α4β2 nicotinic receptors in cognitive decline in Alzheimer’s aetiopathology. Brain 136, 3004–3017 (2013).

Article  PubMed  Google Scholar 

Caulfield, M. P. Muscarinic receptors–characterization, coupling and function. Pharmacol. Ther. 58, 319–379 (1993).

Article  CAS  PubMed  Google Scholar 

Burford, N. T., Tobin, A. B. & Nahorski, S. R. Differential coupling of m1, m2 and m3 muscarinic receptor subtypes to inositol 1,4,5-trisphosphate and adenosine 3′,5′-cyclic monophosphate accumulation in Chinese hamster ovary cells. J. Pharmacol. Exp. Ther. 274, 134–142 (1995).

CAS  PubMed  Google Scholar 

Burford, N. T., Tobin, A. B. & Nahorski, S. R. Coupling of muscarinic m1, m2 and m3 acetylcholine receptors, expressed in Chinese hamster ovary cells, to pertussis toxin-sensitive/insensitive guanine nucleotide-binding proteins. Eur. J. Pharmacol. 289, 343–351 (1995).

Article  CAS  PubMed  Google Scholar 

Gurevich, V. V. & Gurevich, E. V. GPCR signaling regulation: the role of GRKs and arrestins. Front. Pharmacol. 10, 125 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bradley, S. J. et al. Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs. Nat. Chem. Biol. 16, 240–249 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

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, 4524–4529 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Butcher, A. J. et al. Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code. J. Biol. Chem. 286, 11506–11518 (2011).

Article  CAS  PubMed  Google Scholar 

Budd, D. C., Willars, G. B., McDonald, J. E. & Tobin, A. B. Phosphorylation of the Gq/11-coupled m3-muscarinic receptor is involved in receptor activation of the ERK-1/2 mitogen-activated protein kinase pathway. J. Biol. Chem. 276, 4581–4587 (2001).

Article  CAS  PubMed  Google Scholar 

Lin, A. L. et al. Distinct pathways of ERK activation by the muscarinic agonists pilocarpine and carbachol in a human salivary cell line. Am. J. Physiol. Cell Physiol. 294, C1454–C1464 (2008).

Article  CAS  PubMed  Google Scholar 

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, 9440–9445 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

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, 21181–21186 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Smith, J. S., Lefkowitz, R. J. & Rajagopal, S. Biased signalling: from simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. 17, 243–260 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Reiter, E., Ahn, S., Shukla, A. K. & Lefkowitz, R. J. Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors. Annu. Rev. Pharmacol. Toxicol. 52, 179–197 (2012).

Article  CAS  PubMed  Google Scholar 

Berizzi, A. E. et al. Muscarinic M5 receptors modulate ethanol seeking in rats. Neuropsychopharmacology 43, 1510–1517 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Levey, A. I., Edmunds, S. M., Koliatsos, V., Wiley, R. G. & Heilman, C. J. Expression of m1-m4 muscarinic acetylcholine receptor proteins in rat hippocampus and regulation by cholinergic innervation. J. Neurosci. 15, 4077–4092 (1995).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wess, J. Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications. Annu. Rev. Pharmacol. Toxicol. 44, 423–450 (2004).

Article  CAS  PubMed  Google Scholar 

Mesulam, M., Shaw, P., Mash, D. & Weintraub, S. Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann. Neurol. 55, 815–828 (2004).

Article  CAS  PubMed  Google Scholar 

Davies, P. & Maloney, A. J. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2, 1403 (1976).

Article  CAS  PubMed  Google Scholar 

Mufson, E. J., Counts, S. E., Perez, S. E. & Ginsberg, S. D. Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Rev. Neurother. 8, 1703–1718 (2008).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bartus, R. T., Dean, R. L. 3rd, Beer, B. & Lippa,