Altered PKA modulation in the Nav 1 . 1 epilepsy variant

21 Genetic epilepsy with febrile seizures plus (GEFS+) is an inherited epilepsy 22 which can result from mutations in at least four ion channel subunits. The majority of 23 the known GEFS+ mutations have been identified in SCN1A, the gene encoding 24 Nav1.1 α subunit. Protein kinases as critical modulators of sodium channels have been 25 closely related to the genesis of epilepsy. However, little is known about how protein 26 kinases affect GEFS+ mutant sodium channel. To gain insight into the protein kinases 27 effect on channel properties and neuronal excitability of SCN1A mutant channels, we 28 investigated the human SCN1A GEFS+ mutation I1656M by using whole-cell 29 patch-clamp technique and an established computational neuron model. The results 30 showed that the PKA inhibition of sodium current amplitude significantly decreased in 31 the I1656M mutant channels, but the PKC inhibition did not. The responses of the 32 voltage dependent activation and fast inactivation to PKA activator disappeared in the 33 I1656M mutant channels, but the response of the voltage dependence of the slow 34 inactivation did not. Computational model analysis suggested that changes of the 35 I1656M mutant channel gating behaviors in response to PKA activation altered 36 neuronal excitability. These results indicate that altered responses of the mutant 37 channels to PKA signaling may impair the delicate balances between chemical and 38 electrical harmony and lead to abnormal neuronal excitability. 39 40