Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior.
Cell Rep
; 40(10): 111309, 2022 09 06.
Article
in En
| MEDLINE
| ID: mdl-36070693
ABSTRACT
Dysfunctional dopamine signaling is implicated in various neuropsychological disorders. Previously, we reported that dopamine increases D1 receptor (D1R)-expressing medium spiny neuron (MSN) excitability and firing rates in the nucleus accumbens (NAc) via the PKA/Rap1/ERK pathway to promote reward behavior. Here, the results show that the D1R agonist, SKF81297, inhibits KCNQ-mediated currents and increases D1R-MSN firing rates in murine NAc slices, which is abolished by ERK inhibition. In vitro ERK phosphorylates KCNQ2 at Ser414 and Ser476; in vivo, KCNQ2 is phosphorylated downstream of dopamine signaling in NAc slices. Conditional deletion of Kcnq2 in D1R-MSNs reduces the inhibitory effect of SKF81297 on KCNQ channel activity, while enhancing neuronal excitability and cocaine-induced reward behavior. These effects are restored by wild-type, but not phospho-deficient KCNQ2. Hence, D1R-ERK signaling controls MSN excitability via KCNQ2 phosphorylation to regulate reward behavior, making KCNQ2 a potential therapeutical target for psychiatric diseases with a dysfunctional reward circuit.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dopamine
/
KCNQ2 Potassium Channel
/
Mental Disorders
/
Nerve Tissue Proteins
Type of study:
Diagnostic_studies
Limits:
Animals
Language:
En
Journal:
Cell Rep
Year:
2022
Document type:
Article
Affiliation country:
Japan