Altered PKA modulation in the Na(v)1.1 epilepsy variant I1656M.
Genetic epilepsy with febrile seizures plus (GEFS(+)) is an inherited epilepsy that can result from mutations in at least four ion channel subunits. The majority of the known GEFS(+) mutations have been identified in SCN1A, the gene encoding Nav1.1 α-subunit. Protein kinases as critical modulators of sodium channels have been closely related to the genesis of epilepsy. However, little is known about how protein kinases affect the GEFS(+) mutant sodium channel. To gain insight into the protein kinases effect on channel properties and neuronal excitability of SCN1A mutant channels, we investigated the human SCN1A GEFS(+) mutation I1656M by using whole cell patch-clamp technique and an established computational neuron model. The results showed that the PKA inhibition of sodium current amplitude significantly decreased in the I1656M mutant channels, but the PKC inhibition did not. The responses of the voltage-dependent activation and fast inactivation to PKA activator disappeared in the I1656M mutant channels, but the response of the voltage dependence of the slow inactivation did not. Computational model analysis suggested that changes of the I1656M mutant channel gating behaviors in response to PKA activation altered neuronal excitability. 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.
State Key Laboratory of Medical Neurobiology, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai, China.
Shuai
S
Liu
Ping
P
Zheng
D000200:Action Potentials; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D004827:Epilepsy / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating; D008959:Models, Neurological; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology
D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases
GEFS+; Nav1.1; PKA; SCN1A; mutation