Mitogen‐Activated Protein Kinase‐Dependent and Protein Kinase C‐Dependent Pathways Link the m1 Muscarinic Receptor to β‐Amyloid Precursor Protein Secretion
Abstract
Abstract: Full and functionally selective M1 muscarinic agonists (carbachol and AF102B, respectively) activate secretion of the soluble form of amyloid precursor protein (APPs) in PC12 cells expressing the m1 muscarinic receptor (PC12M1 cells). This activation is further augmented by neurotrophins such as nerve growth factor and basic fibroblast growth factor. Muscarinic stimulation activates two transduction pathways that lead to APPs secretion: protein kinase C (PKC)‐dependent and mitogen‐activated protein kinase (MAPK)‐dependent pathways. These pathways operate in parallel and converge with transduction pathways of neurotrophins, resulting in enhancement of APPs secretion when both muscarinic agonist and neurotrophins stimulate PC12M1 cells. These conclusions are supported by the following findings: (a) Only partial blockade of APPs secretion is observed when PKC, p21 ras, or MAPK is fully inhibited by their respective specific inhibitors, GF109203X, S‐trans,trans‐farnesylthiosalicylic acid, and PD98059. (b) K252a, which blocks PKC and phorbol 12‐myristate 13‐acetate‐induced APPs secretion, enhances both muscarinic‐stimulated MAPK activation and APPs secretion. (c) Activation of MAPK in PC12M1 cells by muscarinic agonists is Ras‐dependent but PKC‐independent and is enhanced synergistically by neurotrophins. These results suggest that muscarinic stimulation of APPs secretion is mediated by at least two independent pathways that converge and enhance the signal for APPs secretion at the convergence point.
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M1 muscarinic acetylcholine receptors' regulation of APP processing is at least in part due to ERK signaling pathway activation.
“M1 muscarinic acetylcholine receptors activate the ERK signaling pathway (37), which is at least in part responsible for their regulation of APP processing (38).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [38]
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- Authors
- Haring, R., Fisher, A., Marciano, D., Pittel, Z., Kloog, Y., Zuckerman, A., Eshhar, N., & Heldman, E.
- Affiliations
- Israel Institute for Biological Research (IL)
- Tel Aviv University (IL)
- Corresponding author
- Fisher, Abraham
- Heldman, Eliahu
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1998-11
- Volume
- 71
- Issue
- 5
- Pages
- 2094-2103
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1990343815
- Cited by
- 122
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 4
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- M1 muscarinic receptor, amyloid precursor protein, APP secretion, soluble APP, mitogen-activated protein kinase, protein kinase C, neurotrophins, nerve growth factor, basic fibroblast growth factor, Ras, signal transduction, PC12 cells, carbachol, K252a, PD98059, GF109203X, p21ras
- MeSH terms
- Animals, Carbazoles, Drug Synergism, Enzyme Inhibitors, Nerve Growth Factors, Phosphorylation, Precipitin Tests, Protein Kinase C, Receptors, Muscarinic, Tyrosine, Amyloid beta-Protein Precursor, PC12 Cells, Calcium-Calmodulin-Dependent Protein Kinases, Muscarinic Agonists, Indole Alkaloids, Rats
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