# State-dependent interaction of antiepileptic drugs with voltage-dependent sodium channels and differential regulation of excitatory and inhibitory central neurons

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $474,658

## Abstract

The goal of the proposed research is to take a biophysical approach to understand how antiepileptic
drugs targeted to voltage-dependent sodium channels regulate neuronal firing by differentially binding to
different gating states of the channels. The work brings together two lines of research in the laboratory,
one characterizing the state-dependent interaction of drugs like lidocaine, phenytoin, carbamazepine,
and lacosamide with sodium channels and the other exploring how gating of sodium channels regulates
firing of a variety of mammalian central neurons. A key property of antiepileptic drugs is differential
binding to different gating states of sodium channels, but how this changes firing of particular kinds of
central neurons to control pathological neuronal activity is poorly understood. For example, higher affinity
binding to open and inactivated states results in use-dependence, with increased inhibition as channels
cycle through open and inactivated states during action potentials. Yet, this does not easily explain their
clinical action, because use-dependence might predict more potent inhibition of GABAergic inhibitory
neurons, which typically fire at high frequencies, than glutamatergic excitatory neurons, which typically
fire more slowly. We will examine how antiepileptic drugs interact with the gating of neuronal sodium channels and
explore how state-dependent binding and unbinding regulates the firing patterns of a variety of excitatory
and inhibitory neurons. We will follow up preliminary data showing that carbamazepine, phenytoin, and
lamotrigine are all more effective in inhibiting firing of slower-firing glutamatergic pyramidal neurons than
fast-spiking GABAergic neurons. We will analyze how these drugs and others (including the new anti-
epileptic cannabidiol and a novel, more potent carbamazepine derivative) interact with gating of both
native and cloned sodium channels and how the resulting changes in sodium current modify the firing
patterns of a variety of excitatory and inhibitory neurons in a manner depending on the repertoire of other
channels. The experimental design will combine recordings of action potential firing with voltage-clamp
analysis of the underlying sodium currents, using intact neurons in brain slice, acutely dissociated
neurons, and heterologously expressed cloned channels. A key feature will be to study action potential
firing, channel gating kinetics, and drug action at 37 °C.

## Key facts

- **NIH application ID:** 10104552
- **Project number:** 5R01NS110860-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** BRUCE P BEAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $474,658
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104552

## Citation

> US National Institutes of Health, RePORTER application 10104552, State-dependent interaction of antiepileptic drugs with voltage-dependent sodium channels and differential regulation of excitatory and inhibitory central neurons (5R01NS110860-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104552. Licensed CC0.

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