Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation.
Mutations in SCN1A (encoding the neuronal voltage-gated sodium channel alpha1 subunit, Na(V)1.1, or SCN1A) are associated with genetic epilepsy syndromes including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy. Here, we present the formulation and use of a computational model for SCN1A to elucidate molecular mechanisms underlying the increased persistent sodium current exhibited by the GEFS+ mutant R1648H. Our model accurately reproduces all experimentally measured SCN1A whole-cell biophysical properties including biphasic whole-cell current decay, channel activation, and entry into and recovery from fast and slow inactivation. The model predicts that SCN1A open-state inactivation results from a two-step process that can be conceptualized as initial gate closure, followed by recruitment of a mechanism ("latch") to stabilize the inactivated state. Selective impairment of the second latching step results in an increase in whole-cell persistent current similar to that observed for the GEFS+ mutant R1648H. These results provide a deeper level of understanding of mutant SCN1A dysfunction in an inherited epilepsy syndrome, which will enable more precise computational studies of abnormal neuronal activity in epilepsy and may help guide new targeted therapeutic strategies.
Kahlig
Kristopher M
KM
Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-0275, USA.
Misra
Sunita N
SN
George
Alfred L
AL
D019943:Amino Acid Substitution / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D005544:Forecasting; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D008390:Markov Chains; D008959:Models, Neurological; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels