CGKII Regulates Neuronal Excitability Through Phosphorylating GLUA1 At SER845 And Acts In Epileptic Seizures

The imbalance between excitation and inhibition is a defining feature of epilepsy. GluAl is an AMPA receptors subunit that, when upregulated in the postsynaptic membrane can strengthen excitatory synaptic transmission; this upregulation has been implicated in the pathogenesis of epilepsy. cGKⅡ, a cGMP-dependent protein kinase, can regulate GluAl levels at the plasma membrane. Thus, we hypothesized that cGKⅡ dysfunction is involved in epilepsy. Here, we show that the expression of cGKⅡ, but not cGKI, is upregulated in the epileptogenic brain tissues of both human and rats. Furthermore, in vivo behavior test reveal that rats with intracerebroventricular injection of cGKⅡ agonist 8-Br-cGMP are more susceptible to pilocarpine-induced model of seizures, but cGKⅡ inhibition by KT5823 has the opposite effect. By using in vitro electrophysiological study, cGKII activation can reduce the threshold of 4AP-induced epileptiform discharges, however, cGKⅡ inhibition can weaken the severity of epileptiform activity. Further studies indicated that cGKⅡ activation disrupts the balance of excitation and inhibition due to strengthened AMPAR-mediated excitatory synaptic transmission. Moreover, cGKII regulates epileptic seizures by phosphorylating GluAl at Ser845 to modulate the expression and function of GluAl in the postsynaptic membrane, suggesting that cGKII inhibition is a therapeutic target for epilepsy.