Inhibition by Commercial Aminoglycosides of Human Connexin Hemichannels Expressed in Bacteria.

Mariana Fiori,Guillermo Altenberg,Luis Cuello,Srinivasan Krishnan,Abbey Kjellgren

doi:10.3390/molecules22122063

Abstract

In addition to gap junctional channels that mediate cell-to-cell communication, connexins form hemichannels that are present at the plasma membrane. Since hemichannels are permeable to small hydrophilic compounds, including metabolites and signaling molecules, their abnormal opening can cause or contribute to cell damage in disorders such as cardiac infarct, stroke, deafness, skin diseases, and cataracts. Therefore, hemichannels are potential pharmacological targets. A few aminoglycosides, well-known broad-spectrum antibiotics, have been shown to inhibit hemichannels. Here, we tested several commercially available aminoglycosides for inhibition of human connexin hemichannels using a cell-based bacterial growth complementation assay that we developed recently. We found that kanamycin A, kanamycin B, geneticin, neomycin, and paromomycin are effective inhibitors of hemichannels formed by connexins 26, 43, and 46 (Cx26, Cx43, and Cx46). Because of the >70 years of clinical experience with aminoglycosides and the fact that several of the aminoglycosides tested here have been used in humans, they are promising starting points for the development of effective connexin hemichannel inhibitors.

Highlights

Gap-junction channels (GJCs) and hemichannels (HCs) are connexin oligomers [1,2]
Hemichannels formed by connexin 26 (Cx26), connexin 43 (Cx43), and Cx46 are present in a variety of tissues and organs
We have previously determined the conditions for the growth complementation assay associated with the expression of Cx26 and Cx43 best conditions for the growth complementation assay associated with the expression of Cx26 and

Summary

Introduction

Gap-junction channels (GJCs) and hemichannels (HCs) are connexin oligomers [1,2]. HCs are connexin hexamers, whereas GJCs are formed by docking of two HCs head-to-head (Figure 1).Each of the two HCs of a GJC originates from a different adjacent cell; i.e., each cell contributes one HC to the GJC. Gap-junction channels (GJCs) and hemichannels (HCs) are connexin oligomers [1,2]. The role of GJCs in cell-to-cell communication in health and disease has been known for several decades, but demonstration of undocked, free HCs in the plasma membrane and their role in physiological and pathophysiological processes is more recent [3,4]. Whereas GJCs couple neighboring cells electrically by virtue of their poorly selective permeability to small inorganic ions such as K+ , Cl− , and Na+ [5], HCs (which are mostly closed) are involved in autocrine and paracrine signaling by mediating the regulated efflux of adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD+ ), glutamate, prostaglandins, and other molecules from cells [6]. HCs have been implicated in the pathophysiology of important

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Conclusion