PLPP/CIN-mediated DARPP-32 serine 97 dephosphorylation delays the seizure onset in response to kainic acid in the mouse hippocampus.

Dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32)-mediated protein phosphatase 1 (PP1) inhibition leads to the increase in phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR), which potentiates channel activity and current and thereby may facilitate seizure activity. In the present study, we found that pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN) transiently dephosphorylated DARPP-32 serine (S) 97 site in the early time window, and casein kinase 2 (CK2) subsequently phosphorylated this site in the later time points after kainic acid (KA) injection, which increased the latency of seizure onset in response to KA, but exacerbated the intensity (severity), duration and progression of seizures. TMCB (a CK2 inhibitor) delayed the seizure onset in response to KA, concomitant with the reduced DARPP-32 S97 phosphorylation. Therefore, our findings suggest that PLPP/CIN may play an important role in the latency of seizure onset via DARPP-32-PP1-AMPAR signaling pathway, and may be one of the potential therapeutic targets for medication of seizure or epilepsy. [Display omitted] • PLPP/CIN deletion increased DARPP-32 S97 phosphorylations. • KA increased DARPP-32 T34 and S97 phosphorylations. • KA reduced PLPP/CIN:DARPP-32 binding, but increased DARPP-32:PP1 bindings. • PP1-mediated GRIA1 S845 dephosphorylation was relevant to seizure intensity. • PLPP/CIN and CK2 reversely regulated DARPP-32 S97 phosphorylation. [ABSTRACT FROM AUTHOR]