Block of Voltage-Gated Sodium Channels by Aripiprazole in a State-Dependent Manner

5Citations
Citations of this article
20Readers
Mendeley users who have this article in their library.

Abstract

Aripiprazole is an atypical antipsychotic drug, which is prescribed for many psychiatric diseases such as schizophrenia and mania in bipolar disorder. It primarily acts as an agonist of dopaminergic and other G-protein coupled receptors. So far, an interaction with ligand- or voltage-gated ion channels has been classified as weak. Meanwhile, we identified aripiprazole in a preliminary test as a potent blocker of voltage-gated sodium channels. Here, we present a detailed analysis about the interaction of aripiprazole with the dominant voltage-gated sodium channel of heart muscle (hNav1.5). Electrophysiological experiments were performed by means of the patch clamp technique at human heart muscle sodium channels (hNav1.5), heterologously expressed in human TsA cells. Aripiprazole inhibits the hNav1.5 channel in a state- but not use-dependent manner. The affinity for the resting state is weak with an extrapolated Kr of about 55 µM. By contrast, the interaction with the inactivated state is strong. The affinities for the fast and slow inactivated state are in the low micromolar range (0.5–1 µM). Kinetic studies indicate that block development for the inactivated state must be described with a fast (ms) and a slow (s) time constant. Even though the time constants differ by a factor of about 50, the resulting affinity constants were nearly identical (in the range of 0.5 µM). Besides this, aripirazole also interacts with the open state of the channel. Using an inactivation deficit mutant, an affinity of about 1 µM was estimated. In summary, aripiprazole inhibits voltage-gated sodium channels at low micromolar concentrations. This property might add to its possible anticancer and neuroprotective properties.

References Powered by Scopus

Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches

15824Citations
N/AReaders
Get full text

International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels

1181Citations
N/AReaders
Get full text

Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology

897Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Novel Compounds in the Treatment of Schizophrenia—A Selective Review

14Citations
N/AReaders
Get full text

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

8Citations
N/AReaders
Get full text

The Antidepressant Paroxetine Reduces the Cardiac Sodium Current

2Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Föhr, K. J., Rapp, M., Fauler, M., Zimmer, T., Jungwirth, B., & Messerer, D. A. C. (2022). Block of Voltage-Gated Sodium Channels by Aripiprazole in a State-Dependent Manner. International Journal of Molecular Sciences, 23(21). https://doi.org/10.3390/ijms232112890

Readers over time

‘23‘24‘25036912

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 7

58%

Researcher 5

42%

Readers' Discipline

Tooltip

Agricultural and Biological Sciences 3

30%

Medicine and Dentistry 3

30%

Pharmacology, Toxicology and Pharmaceut... 2

20%

Biochemistry, Genetics and Molecular Bi... 2

20%

Article Metrics

Tooltip
Mentions
News Mentions: 1

Save time finding and organizing research with Mendeley

Sign up for free
0