Dataset Information

Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current I_Na by Lamotrigine; A Potential for Acquired Arrythmias.

ABSTRACT: Lamotrigine is widely prescribed to treat bipolar neurological disorder and epilepsy. It exerts its antiepileptic action by blocking voltage-gated sodium channels in neurons. Recently, the US Food and Drug Administration issued a warning on the use of Lamotrigine after observations of conduction anomalies and Brugada syndrome patterns on the electrocardiograms of epileptic patients treated with the drug. Brugada syndrome and conduction disturbance are both associated with alterations of the cardiac sodium current (I_Na) kinetics and amplitude. In this study, we used the patch clamp technique on cardiomyocytes from epileptic rats to test the hypothesis that Lamotrigine also blocks I_Na in the heart. We found that Lamotrigine inhibited 60% of I_Na peak amplitude and reduced cardiac excitability in epileptic rats but had little effect in sham animals. Moreover, Lamotrigine inhibited 67% of I_NaL and, more importantly, prolonged the action potential refractory period in epileptic animals. Our results suggest that enhanced affinity of Lamotrigine for I_Na may in part explain the clinical phenotypes observed in epileptic patients.

SUBMITTER: Contreras Vite JA

PROVIDER: S-EPMC9609666 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current I<sub>Na</sub> by Lamotrigine; A Potential for Acquired Arrythmias.

Contreras Vite Juan Antonio JA Vega Valle Carlos C Biekeu Mbem Happi H Boivin Sarah-Maude SM Dumaine Robert R

Pharmaceuticals (Basel, Switzerland) 20220929 10

Lamotrigine is widely prescribed to treat bipolar neurological disorder and epilepsy. It exerts its antiepileptic action by blocking voltage-gated sodium channels in neurons. Recently, the US Food and Drug Administration issued a warning on the use of Lamotrigine after observations of conduction anomalies and Brugada syndrome patterns on the electrocardiograms of epileptic patients treated with the drug. Brugada syndrome and conduction disturbance are both associated with alterations of the card ...[more]

PMID: 36297320

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Project description:Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel's selectivity filters to reach the channel's central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed "state-of-the-art" steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure-property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel.

Dataset Information

Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current I_Na by Lamotrigine; A Potential for Acquired Arrythmias.

Publications

Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current I<sub>Na</sub> by Lamotrigine; A Potential for Acquired Arrythmias.

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Dataset Information

Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current INa by Lamotrigine; A Potential for Acquired Arrythmias.

Publications

Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current I<sub>Na</sub> by Lamotrigine; A Potential for Acquired Arrythmias.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current I_Na by Lamotrigine; A Potential for Acquired Arrythmias.