RRC ID 69003
Author Faruk MO, Tsuboi D, Yamahashi Y, Funahashi Y, Lin YH, Ahammad RU, Hossen E, Amano M, Nishioka T, Tzingounis AV, Yamada K, Nagai T, Kaibuchi K.
Title Muscarinic signaling regulates voltage-gated potassium channel KCNQ2 phosphorylation in the nucleus accumbens via protein kinase C for aversive learning.
Journal J Neurochem
Abstract 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 regulate 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.
Volume 160(3)
Pages 325-341
Published 2022-2-1
DOI 10.1111/jnc.15555
PMID 34878647
MeSH Animals Avoidance Learning / physiology* Carbachol / pharmacology Cholinesterase Inhibitors / pharmacology Donepezil / pharmacology KCNQ2 Potassium Channel / genetics KCNQ2 Potassium Channel / metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout Muscarinic Agonists / pharmacology Muscarinic Antagonists / pharmacology Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism* Nucleus Accumbens / metabolism* Parasympathetic Nervous System / physiology* Phosphorylation Protein Kinase C / metabolism* Receptor, Muscarinic M2 / drug effects Receptors, Muscarinic / physiology*
IF 4.066
Mice RBRC02332 RBRC03111