Effects of state-dependent drug block of the NaV1.7 sodium channel on current and action potential behavior in a dynamic clamp in silico DRG neuron

Aberrant sodium channel behavior leading to increased neuronal activity often underlies neurological disorders (e.g., epilepsy and chronic pain). Electrophysiological characterization of drug effects on sodium channel current is not always predictive of how the drug will affect neuronal activity or the drug’s potency. Identifying effective drugs targeting sodium channels requires an understanding of which state (closed, open, inactive) is being affected. To address this issue we used an NaV1.7 Markov model expanded from a conventional Hodgkin-Huxley formulation. We modeled the effects of state-dependent drug binding on sodium channel activation and action potential (AP) behavior in an in silico DRG neuron. Drug binding (kon = 0.0001 nM−1 ms−1, koff = 0.001 ms−1, KD = 10 nM) was modeled to the I1 (inactivated and fully-closed state), I4 (open but inactivated) and O (open) states. Under voltage clamp, NaV1.7 peak current was blocked with IC50 values of 504±12 nM, 805±256 μM and 37.5±0.9 μM, respectively. In contrast, applying a 1 second constant current stimulus and a simulated stochastic synaptic current (Berecki, et al., 2018) to initiate AP firing, drug binding to I1, I4 and open states displayed a higher potency on inhibiting firing with IC50 values of 3.2±0.4 nM, 105±15 nM and 2.9±0.4 μM, respectively. This study suggests there is a wide disparity between drug block under voltage clamp and the inhibitory effects under free running neuronal action potentials. Evaluating drugs targeting mutant sodium channels with altered kinetic behavior could be made patient-specific using this approach. Dynamic clamp and cloned patient-specific mutations can be screened for the desired effects on AP behavior, particularly in conjunction with higher throughput methods such as automated patch clamp.