Muscarinic signaling regulates voltage-gated potassium channel KCNQ2 phosphorylation in the nucleus accumbens via protein kinase C for aversive learning.
Animals
Avoidance Learning
/ physiology
Carbachol
/ pharmacology
Cholinesterase Inhibitors
/ pharmacology
Donepezil
/ pharmacology
KCNQ2 Potassium Channel
/ genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscarinic Agonists
/ pharmacology
Muscarinic Antagonists
/ pharmacology
Nerve Tissue Proteins
/ genetics
Nucleus Accumbens
/ metabolism
Parasympathetic Nervous System
/ physiology
Phosphorylation
Protein Kinase C
/ metabolism
Receptor, Muscarinic M2
/ drug effects
Receptors, Muscarinic
/ physiology
KCNQ2
aversive learning
muscarinic M1 receptors
protein kinase C (PKC)
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
01
12
2021
received:
13
09
2021
accepted:
06
12
2021
pubmed:
9
12
2021
medline:
17
2
2022
entrez:
8
12
2021
Statut:
ppublish
Résumé
The nucleus accumbens (NAc) plays critical roles in emotional behaviors, including aversive learning. Aversive stimuli such as an electric foot shock increase acetylcholine (ACh) in the NAc, and muscarinic signaling appears to increase neuronal excitability and aversive learning. Muscarinic signaling inhibits the voltage-dependent potassium KCNQ current which regulates neuronal excitability, but the regulatory mechanism has not been fully elucidated. Phosphorylation of KCNQ2 at threonine 217 (T217) and its inhibitory effect on channel activity were predicted. However, whether and how muscarinic signaling phosphorylates KCNQ2 in vivo remains unclear. Here, we found that PKC directly phosphorylated KCNQ2 at T217 in vitro. Carbachol and a muscarinic M1 receptor (M1R) agonist facilitated KCNQ2 phosphorylation at T217 in NAc/striatum slices in a PKC-dependent manner. Systemic administration of the cholinesterase inhibitor donepezil, which is commonly used to treat dementia, and electric foot shock to mice induced the phosphorylation of KCNQ2 at T217 in the NAc, whereas phosphorylation was suppressed by an M1R antagonist. Conditional deletion of Kcnq2 in the NAc enhanced electric foot shock induced aversive learning. Our findings indicate that muscarinic signaling induces the phosphorylation of KCNQ2 at T217 via PKC activation for aversive learning.
Substances chimiques
Cholinesterase Inhibitors
0
KCNQ2 Potassium Channel
0
Kcnq2 protein, mouse
0
Muscarinic Agonists
0
Muscarinic Antagonists
0
Nerve Tissue Proteins
0
Receptor, Muscarinic M2
0
Receptors, Muscarinic
0
Donepezil
8SSC91326P
Carbachol
8Y164V895Y
Protein Kinase C
EC 2.7.11.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
325-341Informations de copyright
© 2021 International Society for Neurochemistry.
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