Restoring agonist function at a chemogenetically modified M₁ muscarinic acetylcholine receptor

Khajehali, E., Bradley, S. , van der Westhuizen, E. T., Molloy, C. , Valant, C., Finlayson, L. , Lindsley, C. W., Sexton, P. M., Tobin, A. B. and Christopoulos, A. (2020) Restoring agonist function at a chemogenetically modified M₁ muscarinic acetylcholine receptor. ACS Chemical Neuroscience, 11(24), pp. 4270-4279. (doi: 10.1021/acschemneuro.0c00540) (PMID:33196174)

Abstract

Designer receptors exclusively activated by designer drugs (DREADDs) have been successfully employed to activate signaling pathways associated with specific muscarinic acetylcholine receptor (mAChR) subtypes. The M1 DREADD mAChR displays minimal responsiveness to the endogenous agonist acetylcholine (ACh) but responds to clozapine-N-oxide (CNO), an otherwise pharmacologically inert ligand. We have previously shown that benzyl quinolone carboxylic acid (BQCA), an M1 mAChR positive allosteric modulator (PAM), can rescue ACh responsiveness at these receptors. However, whether this effect is chemotype specific or applies to next-generation M1 PAMs with distinct scaffolds is unknown. Here, we reveal that new M1 PAMs restore ACh function at the M1 DREADD while modulating ACh binding at the M1 wild-type mAChR. Importantly, we demonstrate that the modulation of ACh function by M1 PAMs is translated in vivo using transgenic M1 DREADD mice. Our data provide important insights into mechanisms that define allosteric ligand modulation of agonist affinity vs efficacy and how these effects play out in the regulation of in vivo responses.

• Item Type: Articles
• Additional Information: This work was funded by the Wellcome Trust Collaborative Research Award (no. 201529/Z/16/Z) and a NHMRC Program Grant (Grant 1150083).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Finlayson, Mrs Lisa and Molloy, Mr Colin and Bradley, Dr Sophie and Khajehali, Dr Elham and Tobin, Andrew
• Authors: Khajehali, E., Bradley, S., van der Westhuizen, E. T., Molloy, C., Valant, C., Finlayson, L., Lindsley, C. W., Sexton, P. M., Tobin, A. B., and Christopoulos, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: ACS Chemical Neuroscience
• Publisher: American Chemical Society
• ISSN: 1948-7193
• ISSN (Online): 1948-7193
• Published Online: 16 November 2020

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
173304		Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical Efficacy	Andrew Tobin	Wellcome Trust (WELLCOTR)	201529/Z/16/Z	MCSB - Molecular Pharmacology