Cx46 hemichannel modulation by nitric oxide: Role of the fourth transmembrane helix cysteine and its possible involvement in cataract formation

Retamal, Mauricio A.; Orellana, Viviana P.; Arévalo, Nicolás J.; Rojas, Cristóbal G.; Arjona, Rodolfo J.; Alcaino, Constanza; González, Wendy; Canan, Jonathan; Moraga-Amaro, Rodrigo; Stehberg, Jimmy; Reuss, Luis; Altenberg, Guillermo A.

doi:10.1016/j.niox.2019.02.007

Cited by 10 publications

(14 citation statements)

References 60 publications

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“…Alterations of the lens circulation and subsequent biomineralization in the lens may be affected by modifications of the connexins. The lens fiber connexins can undergo several post-translational modifications, including acetylation, phosphorylation, ubiquitination, carbonylation, nitrosation, and cleavage [43][44][45][46][47][48][49]. Their effect on gap junction or hemichannel function is known in some cases.…”

Section: Cataracts May Results From Biomineralization In the Lensmentioning

confidence: 99%

“…Cleavage can be regulated by phosphorylation [63]. The S-nitrosation of Cx46 (induced with NO donors) increases its hemichannel tail currents and inactivation at positive voltages of 50-60 mV, but does not affect the electrophysiological properties of the Cx46 gap junction channels [48]. The carbonylation of Cx46 (induced with 4-hydroxynonenal) decreases its hemichannel currents and dye uptake [49].…”

Section: Cataracts May Results From Biomineralization In the Lensmentioning

confidence: 99%

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Connexin Mutants Compromise the Lens Circulation and Cause Cataracts through Biomineralization

Berthoud

Gao

Minogue

et al. 2020

IJMS

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Gap junction-mediated intercellular communication facilitates the circulation of ions, small molecules, and metabolites in the avascular eye lens. Mutants of the lens fiber cell gap junction proteins, connexin46 (Cx46) and connexin50 (Cx50), cause cataracts in people and in mice. Studies in mouse models have begun to elucidate the mechanisms by which these mutants lead to cataracts. The expression of the dominant mutants causes severe decreases in connexin levels, reducing the gap junctional communication between lens fiber cells and compromising the lens circulation. The impairment of the lens circulation results in several changes, including the accumulation of Ca2+ in central lens regions, leading to the formation of precipitates that stain with Alizarin red. The cataract morphology and the distribution of Alizarin red-stained material are similar, suggesting that the cataracts result from biomineralization within the organ. In this review, we suggest that this may be a general process for the formation of cataracts of different etiologies.

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Section: Cataracts May Results From Biomineralization In the Lensmentioning

confidence: 99%

Section: Cataracts May Results From Biomineralization In the Lensmentioning

confidence: 99%

Connexin Mutants Compromise the Lens Circulation and Cause Cataracts through Biomineralization

Berthoud

Gao

Minogue

et al. 2020

IJMS

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“…Suggesting that any posttranslational modification in the extracellular loop 1 could modulate (in any direction) the Ca 2+ sensor effect. Recently, our group suggested that the S-nitrosylation of Cx46 hemichannels could play an important role in cataract formation [90]. In summary, pathological conditions, such as mutations and inflammation, can induce leaky hemichannels leading to cell injury.…”

Section: Hemichannelsmentioning

confidence: 99%

Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?

Rozas-Villanueva

Casanello

Retamal

2020

IJMS

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Preeclampsia is a pregnancy complication that appears after 20 weeks of gestation and is characterized by hypertension and proteinuria, affecting both mother and offspring. The cellular and molecular mechanisms that cause the development of preeclampsia are poorly understood. An important feature of preeclampsia is an increase in oxygen and nitrogen derived free radicals (reactive oxygen species/reactive nitrogen species (ROS/RNS), which seem to be central players setting the development and progression of preeclampsia. Cell-to-cell communication may be disrupted as well. Connexins (Cxs), a family of transmembrane proteins that form hemichannels and gap junction channels (GJCs), are essential in paracrine and autocrine cell communication, allowing the movement of signaling molecules between cells as well as between the cytoplasm and the extracellular media. GJCs and hemichannels are fundamental for communication between endothelial and smooth muscle cells and, therefore, in the control of vascular contraction and relaxation. In systemic vasculature, the activity of GJCs and hemichannels is modulated by ROS and RNS. Cxs participate in the development of the placenta and are expressed in placental vasculature. However, it is unknown whether Cxs are modulated by ROS/RNS in the placenta, or whether this potential modulation contributes to the pathogenesis of preeclampsia. Our review addresses the possible role of Cxs in preeclampsia, and the plausible modulation of Cxs-formed channels by ROS and RNS. We suggest these factors may contribute to the development of preeclampsia.

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“…Abnormally high connexin HC activity plays a role in the cell damage observed in deafness, skin diseases, cataracts, cardiac infarcts, cerebrovascular accidents, neurodegenerative diseases, and conditions characterized by inflammation and oxidative stress in general (Beyer & Berthoud, ; Lee & White, ; Orellana et al., ; Retamal et al., , ; Schulz et al., ; Shintani‐Ishida et al., ; Vergara et al., ). In spite of their recognition as potential pharmacological targets to aid in the treatment of the disorders mentioned above, the discovery and development of connexin HC inhibitors has been slow.…”

Section: Commentarymentioning

confidence: 99%

“…However, abnormally sustained opening of HCs can contribute to cell damage in conditions characterized by hypoxia and oxidative stress, including cardiac infarcts and stroke (Fig. ) (Beyer & Berthoud, ; Lee & White, ; Orellana, Avendano, & Montero, ; Retamal et al., ; Retamal, Bennett, Pelegrin, & Fernandez, ; Schulz et al., ; Shintani‐Ishida, Uemura, & Yoshida, ; Vergara, Bao, Bello‐Reuss, & Reuss, ). Therefore, HC inhibitors that can be used, for example, to minimize ischemic damage in the heart and brain are desirable.…”

Section: Introductionmentioning

confidence: 99%

A Simple Assay to Evaluate the Function of Human Connexin Hemichannels Expressed in Escherichia coli that Can Be Used for Drug Discovery and Mutant Analysis

2019

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Abnormally increased activity of connexin hemichannels contributes to cell damage in many disorders, including deafness, stroke, and cardiac infarct, and therefore hemichannels constitute a potentially important therapeutic target. Unfortunately, the available hemichannel inhibitors are not specific and most are toxic. The absence of a simple and cost‐effective screening assay has made the discovery of hemichannel inhibitors difficult. Here, we present an optimized assay where human connexins are expressed in genetically modified Escherichia coli cells deficient in potassium uptake (LB2003 cells). These cells cannot grow in low‐potassium medium, and hemichannel function is assayed by the reversion of the no‐growth phenotype. Since functional hemichannels are permeable to potassium, they allow for its uptake and cell growth. The simple reading of bacterial growth in low‐potassium medium distinguishes functional hemichannels (growth) from those inhibited (no growth). This assay is simple, robust, inexpensive, and reliable, and is easily scaled to high‐throughput multiwell platforms. © 2019 by John Wiley & Sons, Inc. Basic Protocol 1: Preparation of competent LB2003 cells resistant to kanamycin Basic Protocol 2: Growth complementation assay Support Protocol: Evaluation of cytotoxic effects of potential connexin hemichannel inhibitors

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Cx46 hemichannel modulation by nitric oxide: Role of the fourth transmembrane helix cysteine and its possible involvement in cataract formation

Cited by 10 publications

References 60 publications

Connexin Mutants Compromise the Lens Circulation and Cause Cataracts through Biomineralization

Connexin Mutants Compromise the Lens Circulation and Cause Cataracts through Biomineralization

Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?

A Simple Assay to Evaluate the Function of Human Connexin Hemichannels Expressed in Escherichia coli that Can Be Used for Drug Discovery and Mutant Analysis

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