ArticleProceedings of the National Academy of Sciences of the United States of America2010
The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
67 citing papers in PubMed, 1 synthesis or guideline pooled it, 144 citations in OpenAlex.
- The cellular model for Alzheimer's disease research: PC12 cells.Frontiers in molecular neuroscience · 2022Pooled it
- Biperiden Challenge Model in Healthy Elderly as Proof-of-Pharmacology Tool: A Randomized, Placebo-Controlled Trial.Journal of clinical pharmacology · 2021Trial
- Neurotransmitters and Immunity: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- Primary Cilia and Cardiovascular Risk Factors in Alzheimer's Disease.Brain sciences · 2025Review
- Development of Mutant MBiochemistry · 2025Article
- AiGPro: a multi-tasks model for profiling of GPCRs for agonist and antagonist.Journal of cheminformatics · 2025Article
- A golden age of muscarinic acetylcholine receptor modulation in neurological diseases.Nature reviews. Drug discovery · 2024Review
- Impacts of sex differences on optogenetic, chemogenetic, and calcium-imaging tools.Current opinion in neurobiology · 2024Review
- Review
- Article
- Cholinergic Antagonists and Behavioral Disturbances in Neurodegenerative Diseases.International journal of molecular sciences · 2023Review
- Muscarinic antagonists impair multiple aspects of operant discrimination learning and performance.Neuroscience letters · 2023Article
- Liver's influence on the brain through the action of bile acids.Frontiers in neuroscience · 2023Review
- Modulation of Muscarinic Signalling in the Central Nervous System by Steroid Hormones and Neurosteroids.International journal of molecular sciences · 2022Review
- PD 102807 Induces M3 mAChR-Dependent GRK-/Arrestin-Biased Signaling in Airway Smooth Muscle Cells.American journal of respiratory cell and molecular biology · 2022Article
- G protein-biased GPR3 signaling ameliorates amyloid pathology in a preclinical Alzheimer's disease mouse model.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Targeting the M1 muscarinic acetylcholine receptor in Alzheimer's disease.Neuronal signaling · 2022Review
- QR code model: a new possibility for GPCR phosphorylation recognition.Cell communication and signaling : CCS · 2022Review
- Understanding How Physical Exercise Improves Alzheimer's Disease: Cholinergic and Monoaminergic Systems.Frontiers in aging neuroscience · 2022Review
- The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure.Frontiers in cellular neuroscience · 2022Article
7 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer's disease. This pathology is thought to be linked to a loss of signaling through the cholinergic M(1)-muscarinic receptor subtype. However, recent studies have cast doubt on whether this is the primary receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M(3)-muscarinic receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M(3)-muscarinic receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M(3)-muscarinic receptor in this process involves receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient receptor mutant also shows a deficit in fear conditioning. Consistent with a role for receptor phosphorylation, we demonstrate that the M(3)-muscarinic receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M(3)-muscarinic receptor was coupled normally to G(q/11)-signaling but was uncoupled from phosphorylation-dependent processes such as receptor internalization and arrestin recruitment. It can, therefore, be concluded that M(3)-muscarinic receptor-dependent learning and memory depends, at least in part, on receptor phosphorylation/arrestin signaling. This study opens the potential for biased M(3)-muscarinic receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.