Over-activated hemichannels: A possible therapeutic target for human diseases

Retamal, Mauricio A.; Fernández-Olivares, Ainoa; Stehberg, Jimmy

doi:10.1016/j.bbadis.2021.166232

Cited by 12 publications

(8 citation statements)

References 206 publications

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“…In this work, we developed a novel all-optical assay to probe Ca 2+ uptake through normal or pathological HCs, which are emerging drug targets for a variety of pathological conditions [41][42][43][44][45][46][47][48][49]61,62], using cytosolic GCaMP6s fluorescence intensity variations as a readout. This choice was dictated by different considerations.…”

Section: Discussionmentioning

confidence: 99%

“…Deregulated Ca 2+ flux through HCs has been implicated in several diseases linked to Cx mutations [18,[38][39][40]. In addition, the opening of wild type (wt) Cx HCs is associated with an impressive list of pathological conditions that affect a major proportion of the world population, including ischemia/stroke, Alzheimer's disease, epilepsy, liver fibrosis and cirrhosis, nonalcoholic steatohepatitis, inflammation and others [41][42][43][44][45][46]. Of note, inhibition of Cx HCs in animal models in vivo exerted anticonvulsant effects [47], lowered the degree of liver fibrosis induced by administration of thioacetamide [48] and improved recovery from spinal cord injury [49].…”

Section: Introductionmentioning

confidence: 99%

“…The Ca 2+ uptake assay we developed provides a highly sensitive readout of Cx HC activity, as detailed hereafter. Furthermore, the assay is also suitable to evaluate the efficacy of different HC inhibitors that are attracting a growing attention as potential therapeutics [41][42][43][44][45][46][47][48], including antibodies targeting the extracellular domain of HCs [49,[59][60][61][62].…”

Section: Introductionmentioning

confidence: 99%

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A Quantitative Assay for Ca2+ Uptake through Normal and Pathological Hemichannels

Nardin

Tettey-Matey

Donati

et al. 2022

IJMS

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Connexin (Cx) hemichannels (HCs) are large pore hexameric structures that allow the exchange of ions, metabolites and a variety of other molecules between the cell cytoplasm and extracellular milieu. HC inhibitors are attracting growing interest as drug candidates because deregulated fluxes through HCs have been implicated in a plethora of genetic conditions and other diseases. HC activity has been mainly investigated by electrophysiological methods and/or using HC-permeable dye uptake measurements. Here, we present an all-optical assay based on fluorometric measurements of ionized calcium (Ca2+) uptake with a Ca2+-selective genetically encoded indicator (GCaMP6s) that permits the optical tracking of cytosolic Ca2+ concentration ([Ca2+]cyt) changes with high sensitivity. We exemplify use of the assay in stable pools of HaCaT cells overexpressing human Cx26, Cx46, or the pathological mutant Cx26G45E, under control of a tetracycline (Tet) responsive element (TRE) promoter (Tet-on). We demonstrate the usefulness of the assay for the characterization of new monoclonal antibodies (mAbs) targeting the extracellular domain of the HCs. Although we developed the assay on a spinning disk confocal fluorescence microscope, the same methodology can be extended seamlessly to high-throughput high-content platforms to screen other kinds of inhibitors and/or to probe HCs expressed in primary cells and microtissues.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Quantitative Assay for Ca2+ Uptake through Normal and Pathological Hemichannels

Nardin

Tettey-Matey

Donati

et al. 2022

IJMS

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“…Pathological conditions can diminish or enhance molecular pathways associated to these modifications and alter Cx46-based channel properties, which in turn can produce ion and metabolites disbalances. Therefore, understanding the molecular mechanisms of Cx46 regulation could benefit future new therapies against cataracts ( Retamal et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, increased hemichannel opening can lead to the development of cataracts due to damaging disbalances that result from changes that include increases in Na + and Ca 2+ influxes, losses of K + , ATP and GSH, and depolarization ( Figure 4 ). Hyperactive hemichannels can be the result of mutations or a variety of mechanisms that include membrane depolarization, increases in intracellular Ca 2+ , and changes in the phosphorylation and redox status ( Bao L. et al, 2004 ; Bukauskas and Verselis, 2004 ; Saez et al, 2005 ; Berthoud and Beyer, 2009 ; Fasciani et al, 2013 ; Retamal et al, 2015 ; Figueroa et al, 2019 ; Berthoud et al, 2020 ; Peracchia, 2020 ; Natha et al, 2021 ; Retamal et al, 2021 ). Overall, the information available supports a role of Cx46 hemichannels in the lens.…”

Section: Connexins In the Lensmentioning

confidence: 99%

Role and Posttranslational Regulation of Cx46 Hemichannels and Gap Junction Channels in the Eye Lens

Retamal

Altenberg

2022

Front. Physiol.

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Connexins are a family of proteins that can form two distinct types of channels: hemichannels and gap junction channels. Hemichannels are composed of six connexin subunits and when open allow for exchanges between the cytoplasm and the extracellular milieu. Gap junction channels are formed by head-to-head docking of two hemichannels in series, each one from one of two adjacent cells. These channels allow for exchanges between the cytoplasms of contacting cells. The lens is a transparent structure located in the eye that focuses light on the retina. The transparency of the lens depends on its lack of blood irrigation and the absence of organelles in its cells. To survive such complex metabolic scenario, lens cells express Cx43, Cx46 and Cx50, three connexins isoforms that form hemichannels and gap junction channels that allow for metabolic cooperation between lens cells. This review focuses on the roles of Cx46 hemichannels and gap junction channels in the lens under physiological conditions and in the formation of cataracts, with emphasis on the modulation by posttranslational modifications.

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Purification, Reconstitution, and Functional Analysis of Connexin Hemichannels

Fiori,

Altenberg

2024

Methods in Molecular Biology

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Over-activated hemichannels: A possible therapeutic target for human diseases

Cited by 12 publications

References 206 publications

A Quantitative Assay for Ca2+ Uptake through Normal and Pathological Hemichannels

A Quantitative Assay for Ca2+ Uptake through Normal and Pathological Hemichannels

Role and Posttranslational Regulation of Cx46 Hemichannels and Gap Junction Channels in the Eye Lens

Purification, Reconstitution, and Functional Analysis of Connexin Hemichannels

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