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Familial inherited epilepsy with febrile seizures plus (GEFS+) caused by the mutation (I1656M) in SCN1A, the gene encoding the brain vohage-gated sodium channel α1 subunit, has received a considerable attention because it provides a novel epileptic model to understand the pathogenesis of epilepsy.Previous studies examined biophysical characteristics of I 1656M using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A.In the present paper, we examined changes of channel properties in responses to cAMP-dependent protein kinase (PKA) activator forskolin and protein kinase C (PKC) activator PDBu in the mutant channels by using whole-cell patch-clamp technique.The results showed that the response of the amplitude of sodium currents to forskolin significantly decreased in the mutant channels, but did not to PDBu.In addition, the response of the voltage dependence of activation and fast inactivation to forskolin disappeared in mutant channels, but the response of the voltage dependence of slow inactivation did not.The overall effect of PKA activation on neuronal excitability were opposite in the mutant channels.These results indicate that altered responses of the mutant channels to PKA signaling may impair the delicate balances between chemical and electrical harmony and lead to abnormal neuronal excitability.