Impaired Inactivation Gate Stabilization Predicts Increased Persistent Current for an Epilepsy-AssociatedSCN1AMutation

Abstract

Mutations in SCN1A (encoding the neuronal voltage-gated sodium channel ␣ 1 subunit, Na V 1.1, or SCN1A) are associated with genetic epilepsy syndromes including generalized epilepsy with febrile seizures plus (GEFSϩ) 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 GEFSϩ 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 GEFSϩ 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.

Ranolazine block of human Nav1.4 sodium channels and paramyotonia congenita mutants

“…31 Skeletal muscle simulations using the WT-Na v 1.4 and Mutant-Na v 1.4 models 4 (D). In all experiments the total sodium conductance was held constant and action potentials were elicited by a 100 msec depolarizing current injection.…”

“…The original Hodgkin-Huxley Na v channel model was replaced by our Markov models for Na v 1.4. All implementation parameters were identical to the original report 31 unless otherwise noted. All simulations were performed within the NEURON simulation environment (www.neuron.yale.edu) using the CVODE variable time step routine.…”

“…44 Markov models of WT-Na v 1.4 and Mutant-Na v 1.4 were constructed using our previously described model of Na v 1.1 as a template. 31 This approach was feasible as recombinant hNa v 1.1 and hNa v 1.4 channels share many aspects of channel function including rapid activation and inactivation kinetics (Figs. 1-4 , respectively).…”

Ranolazine Reduces Neuronal Excitability by Interacting with Inactivated States of Brain Sodium Channels

“…The reported model accurately reproduces all recorded behaviors of heterologously expressed brain Na V channels (Supplemental Fig. 3) (Kahlig et al, 2006). For action potential simulations, we used the somatic compartment of the previously published model of a pyramidal neuron (Uebachs et al, 2010).…”

“…Computational Modeling. The computational model reported here for a brain Na V channel is based on our previously described model of human brain Na V 1.1 (Kahlig et al, 2006). The model has been simplified and generalized to allow better quantitation of drug binding to fast-inactivated and slow-inactivated states (Fig.…”