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Author Notes:

To whom correspondence should be addressed. Woodruff Memorial Research Building, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322. Fax: 404-727-3999. E-mail: alevey@emory.edu.


Research Funding:

This work was supported by the National Institutes of Health [NS030454 and F30AG297313] and a predoctoral fellowship from the Pharmaceutical and Research Manufacturers of America (PhRMA).


  • Muscarinic
  • acetylcholine
  • receptor
  • allosteric
  • arrestin
  • internalization

Differential Effects of Allosteric M1 Muscarinic Acetylcholine Receptor Agonists on Receptor Activation, Arrestin 3 Recruitment, and Receptor Downregulation


Journal Title:

ACS Chemical Neuroscience


Volume 1, Number 8


, Pages 542-551

Type of Work:

Article | Post-print: After Peer Review


Muscarinic acetylcholine receptors (mAChRs) are drug targets for multiple neurodegenerative and neuropsychiatric disorders, but the full therapeutic potential of mAChR-targeted drugs has not been realized, mainly because of a lack of subtype-selective agonists. Recent advances have allowed the development of highly selective agonists that bind to an allosteric site on the M1 mAChR that is spatially distinct from the orthosteric acetylcholine binding site, but less is known about the profile of intracellular signals activated by orthosteric versus allosteric M1 mAChR agonists. We investigated the activation and regulatory mechanisms of two structurally distinct allosteric M1 mAChR agonists, AC260584 and TBPB. We show that allosteric agonists potently activate multiple signal transduction pathways linked to the M1 mAChR receptor but, compared to orthosteric agonists, much less efficiently recruit arrestin 3, a protein involved in the regulation of G-protein coupled receptor signaling. Consistent with decreased arrestin recruitment, both allosteric agonists showed blunted responses in measurements of receptor desensitization, internalization, and downregulation. These results advance the understanding of mAChR biology and may shed light on unanticipated differences in the pharmacology of orthosteric versus allosteric agonists that might be capitalized upon for drug development for the treatment of CNS diseases.

Copyright information:

© 2010 American Chemical Society

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