| RRC ID |
81086
|
| 著者 |
Yamahashi Y, Lin YH, Mouri A, Iwanaga S, Kawashima K, Tokumoto Y, Watanabe Y, Faruk MO, Zhang X, Tsuboi D, Nakano T, Saito N, Nagai T, Yamada K, Kaibuchi K.
|
| タイトル |
Phosphoproteomic of the acetylcholine pathway enables discovery of the PKC-β-PIX-Rac1-PAK cascade as a stimulatory signal for aversive learning.
|
| ジャーナル |
Mol Psychiatry
|
| Abstract |
Acetylcholine is a neuromodulator critical for learning and memory. The cholinesterase inhibitor donepezil increases brain acetylcholine levels and improves Alzheimer's disease (AD)-associated learning disabilities. Acetylcholine activates striatal/nucleus accumbens dopamine receptor D2-expressing medium spiny neurons (D2R-MSNs), which regulate aversive learning through muscarinic receptor M1 (M1R). However, how acetylcholine stimulates learning beyond M1Rs remains unresolved. Here, we found that acetylcholine stimulated protein kinase C (PKC) in mouse striatal/nucleus accumbens. Our original kinase-oriented phosphoproteomic analysis revealed 116 PKC substrate candidates, including Rac1 activator β-PIX. Acetylcholine induced β-PIX phosphorylation and activation, thereby stimulating Rac1 effector p21-activated kinase (PAK). Aversive stimulus activated the M1R-PKC-PAK pathway in mouse D2R-MSNs. D2R-MSN-specific expression of PAK mutants by the Cre-Flex system regulated dendritic spine structural plasticity and aversive learning. Donepezil induced PAK activation in both accumbal D2R-MSNs and in the CA1 region of the hippocampus and enhanced D2R-MSN-mediated aversive learning. These findings demonstrate that acetylcholine stimulates M1R-PKC-β-PIX-Rac1-PAK signaling in D2R-MSNs for aversive learning and imply the cascade's therapeutic potential for AD as aversive learning is used to preliminarily screen AD drugs.
|
| 巻・号 |
27(8)
|
| ページ |
3479-3492
|
| 公開日 |
2022-8-1
|
| DOI |
10.1038/s41380-022-01643-2
|
| PII |
10.1038/s41380-022-01643-2
|
| PMID |
35665767
|
| PMC |
PMC9708603
|
| MeSH |
Acetylcholine*
Animals
Brain
Donepezil / pharmacology
Mice
Protein Kinase C
p21-Activated Kinases*
|
| IF |
12.384
|
| リソース情報 |
| 実験動物マウス |
RBRC02332 |
