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GPCR SIGNALING

Leveraging bias to your advantage

Nature Chemical Biology volume 16, pages 226–227 (2020)Cite this article

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Characterization of biased receptor signaling has ushered in opportunities for unprecedented control of G-protein-coupled receptors. Elucidation of distinct M1 muscarinic acetylcholine receptor signaling pathways and development of biased ligands may offer novel and safer Alzheimer’s disease therapeutics.

The M1 muscarinic acetylcholine receptor (mAChR) has attracted intense interest as a promising therapeutic target for the treatment of the cognitive disruptions in schizophrenia and Alzheimer’s disease (AD)1. Small molecules that target the M1 mAChR can display a diverse range of pharmacological properties, some of which are potentially detrimental to in vivo efficacy. Therefore, there is a critical need to understand the subtle pharmacological properties of distinct M1 ligands and characterize the diverse signaling pathways downstream of the M1 mAChR. Bradley et al. report that M1 mAChR phosphorylation-dependent signaling, crucial for interactions with arrestin, might be critical for efficacy of M1 activators2. Conversely, studies using small molecules biased toward M1-dependent G-protein signaling, and genetic deletion of phosphorylation sites on M1, provide evidence that G-protein signaling mediates M1-dependent adverse events.

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Fig. 1: Probing the signaling pathway(s) that mediate the effects of M1 mAChR modulation.

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Authors and Affiliations

  1. Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA

    Sean P. Moran & P. Jeffrey Conn

  2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA

    Sean P. Moran & P. Jeffrey Conn

  3. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    P. Jeffrey Conn

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  1. Sean P. Moran
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  2. P. Jeffrey Conn
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Correspondence to P. Jeffrey Conn.

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Moran, S.P., Conn, P.J. Leveraging bias to your advantage. Nat Chem Biol 16, 226–227 (2020). https://doi.org/10.1038/s41589-020-0468-2

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  • DOI: https://doi.org/10.1038/s41589-020-0468-2

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