Differential effects of allosteric M(1) muscarinic acetylcholine receptor agonists on receptor activation, arrestin 3 recruitment, and receptor downregulation.
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 M(1) 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 M(1) mAChR agonists. We investigated the activation and regulatory mechanisms of two structurally distinct allosteric M(1) mAChR agonists, AC260584 and TBPB. We show that allosteric agonists potently activate multiple signal transduction pathways linked to the M(1) mAChR receptor but, compared to orthosteric agonists, much less efficiently recruit arrestin 3, a protein involved in 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 vs. allosteric agonists that might be capitalized upon for drug development for the treatment of CNS diseases.
Davis
Albert A
AA
Center for Neurodegenerative Disease and Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322.
Heilman
Craig J
CJ
Brady
Ashley E
AE
Miller
Nicole R
NR
Fuerstenau-Sharp
Maya
M
Hanson
Bonnie J
BJ
Lindsley
Craig W
CW
Conn
P Jeffrey
PJ
Lah
James J
JJ
Levey
Allan I
AI