Inhibition of gap junctional intercellular communication by an anti-migraine agent, flunarizine.

Joo Hye Yeo,Eun Ju Choi,Jinu Lee,Michael Koval

doi:10.1371/journal.pone.0222326

Abstract

Gap junctions (GJs), which consist of proteins called connexins, are intercellular channels that allow the passage of ions, second messengers, and small molecules. GJs and connexins are considered as emerging therapeutic targets for various diseases. Previously, we screened numerous compounds using our recently developed iodide yellow fluorescent protein gap junctional intercellular communication (I-YFP GJIC) assay and found that flunarizine (FNZ), used for migraine prophylaxis and as an add-on therapy for epilepsy, inhibits GJIC in LN215 human glioma cells. In this study, we confirmed that FNZ inhibits GJIC using the I-YFP GJIC assay. We demonstrated that FNZ inhibits GJ activities via a mechanism that is independent of calcium channels and dopaminergic D2, histaminergic H1, or 5-HT receptors. In addition, we showed that FNZ significantly increases connexin 43 (Cx43) phosphorylation on the cell surface, but does not alter the total amount of Cx43. The beneficial effects of FNZ on migraines and epilepsy might be related to GJ inhibition.

Highlights

Gap junctions (GJs) mediate cell-to-cell communication, known as gap junctional intercellular communication (GJIC), which enables the exchange of small molecules (< 1 kDa), including ions, metabolites, and nutrients, between the cytoplasm of adjacent cells
SLC26A can exhibit artifactual GJIC inhibition, we examined whether FNZ inhibits SLC26A4
The present study demonstrated GJIC inhibition by FNZ, as well as experimental results related to its mechanism of action

Summary

Introduction

Gap junctions (GJs) mediate cell-to-cell communication, known as gap junctional intercellular communication (GJIC), which enables the exchange of small molecules (< 1 kDa), including ions, metabolites, and nutrients, between the cytoplasm of adjacent cells. GJs or connexins play crucial roles in the development, growth control, and homeostasis of tissues and organs, as well as the pathophysiology of various diseases including cardiovascular diseases, such as hypertrophic cardiomyopathy, heart failure, and myocardial infarction [2];[3]; particular subtypes of epilepsy [4]; migraine with aura [5]; non-neoplastic liver diseases [6]; wound healing [7]; glaucoma [8]; non-syndromic deafness [9]; X-linked Charcot-Marie Tooth disease [10]; and oculodentodigital dysplasia (ODDD) [11];[12]. There is a growing interest in developing new pharmaceuticals that can modulate GJs

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