Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

Vuyst, Elke De; Boengler, Kerstin; Antoons, Gudrun; Sipido, Karin R.; Schulz, Rainer; Leybaert, Luc

doi:10.1111/j.1476-5381.2011.01244.x

Cited by 84 publications

(78 citation statements)

References 137 publications

(156 reference statements)

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“…Based on our present results, we therefore selected mitochondrial Cx43. Although some compounds have been described that stimulate Cx43 and increase gap junction coupling, they also exert diverse Cx43-unrelated actions and/or their molecular targets remain elusive (26,27). Therefore, we chose RRNYRRNY, an RXP-related peptide that binds to the Cx43 C terminus (13,28).…”

Section: See Retraction Published December 10 2012mentioning

confidence: 99%

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Rottlaender

Boengler²,

Wolny³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Section: See Retraction Published December 10 2012mentioning

confidence: 99%

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Rottlaender

Boengler²,

Wolny³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…9 Multiple lines of evidence suggest that connexins could be targeted pharmacologically for treating many diseases. 10,11 For example, antiarrhythmic peptides, such as AAP10, have been shown to increase GJ conductance in cardiomyocytes and heterologously expressed Cx43 and Cx45 but not Cx40. 12 An orally available nonpeptide analogue of AAP10, gap-134, improves conduction and reduces atrial fibrillation/flutter in the canine sterile pericarditis model, 13 and is used in clinical trials for atrial fibrillation.…”

Section: Introductionmentioning

confidence: 99%

A High-Throughput Assay for Connexin 43 (Cx43,GJA1) Gap Junctions Using Codon-Optimized Aequorin

Haq

Grose²,

Ward³

et al. 2013

ASSAY and Drug Development Technologies

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Gap junctions (GJs) are intercellular channels which are composed of the connexin family of proteins that allow electrical and chemical communications and synchronization in tissue ensembles. Evidence suggests that pharmaceutical modulators of these channels may have therapeutic potential or carry undesired liability. In this report, we exogenously expressed human connexin 43 (Cx43, GJA1) and demonstrated functionality in a 96-well flow cytometry assay detecting intercellular transfer of the calcein dye. We have designed a 384-well high-throughput method for detecting the transfer of calcium between HeLa cells expressing Cx43. In this assay, donor cells coexpress Cx43 and the α1A adrenergic Gα-coupled receptor, while recipient cells coexpress Cx43 and the cytoplasmic version of the calcium-sensitive luminescent protein aequorin enhanced by codon optimization (cytoAeq). The two cell populations were mixed, dispensed to 384-well plates, and incubated for 3 h to allow the formation of GJs. Activation of α1A by epinephrine in donor cells led to dose-dependent calcium increases in recipient cells, which were detected by measuring the intensity of aequorin luminescence. The response was dependent on the expression of Cx43 and inhibited by the GJ blocker 18α-glycyrrhetinic acid, suggesting Cx43 GJ-mediated activity. In a parallel experiment with capsaicin and the TrpV1 ion channel in place of phenylephrine and α1A, a similar magnitude of difference in the maximal calcium response was detected in both donor and recipient cells, suggesting that calcium is likely the permeant ion through the GJ. This assay may pave the way for high-throughput screening of GJ modulators for drug discovery.

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“…Eventually, several of these drugs may not necessarily work, at least under the same concentration and exposure conditions, in all cell types. It is also intriguing that, so far, few connexin channel "openers" have been clearly identified (117,119,124,206,292,432), which delays the development of future strategies aimed at developing a connexin-targeted therapy of several diseases, specifically in humans.…”

Section: G the Pharmacologymentioning

confidence: 99%

Connexins: Key Mediators of Endocrine Function

Bosco

Haefliger

Meda

2011

Physiological Reviews

156

185

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The appearance of multicellular organisms imposed the development of several mechanisms for cell-to-cell communication, whereby different types of cells coordinate their function. Some of these mechanisms depend on the intercellular diffusion of signal molecules in the extracellular spaces, whereas others require cell-to-cell contact. Among the latter mechanisms, those provided by the proteins of the connexin family are widespread in most tissues. Connexin signaling is achieved via direct exchanges of cytosolic molecules between adjacent cells at gap junctions, for cell-to-cell coupling, and possibly also involves the formation of membrane “hemi-channels,” for the extracellular release of cytosolic signals, direct interactions between connexins and other cell proteins, and coordinated influence on the expression of multiple genes. Connexin signaling appears to be an obligatory attribute of all multicellular exocrine and endocrine glands. Specifically, the experimental evidence we review here points to a direct participation of the Cx36 isoform in the function of the insulin-producing β-cells of the endocrine pancreas, and of the Cx40 isoform in the function of the renin-producing juxtaglomerular epithelioid cells of the kidney cortex.

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Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

Cited by 84 publications

References 137 publications

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

A High-Throughput Assay for Connexin 43 (Cx43,GJA1) Gap Junctions Using Codon-Optimized Aequorin

Connexins: Key Mediators of Endocrine Function

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Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

Cited by 84 publications

References 137 publications

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K + channels

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K + channels

A High-Throughput Assay for Connexin 43 (Cx43,GJA1) Gap Junctions Using Codon-Optimized Aequorin

Connexins: Key Mediators of Endocrine Function

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Product

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RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels