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Nitric Oxide. 2019 May 1;86:54-62. doi: 10.1016/j.niox.2019.02.007. Epub 2019 Feb 21.

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

Author information

1
Centro de Fisiología Celular e Integrativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile; Department of Cell Physiology and Molecular Biophysics, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, Texas, USA; Programa de Comunicación Celular en Cáncer, Instituto de Ciencias e Innovación en Medicina (ICIM), Santiago, Chile. Electronic address: mretamal@udd.cl.
2
Centro de Fisiología Celular e Integrativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
3
Centro de Fisiología Celular e Integrativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile; Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, 55905, USA.
4
Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Talca, Chile; Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Chile.
5
Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Talca, Chile.
6
Laboratorio de Neurobiología, Instituto de Investigaciones Médicas, Facultad de Ciencias de la vida and Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile.
7
Department of Cell Physiology and Molecular Biophysics, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.

Abstract

Under normal conditions, connexin (Cx) hemichannels have a low open probability, which can increase under pathological conditions. Since hemichannels are permeable to relatively large molecules, their exacerbated activity has been linked to cell damage. Cx46 is highly expressed in the lens and its mutations have been associated to cataract formation, but it is unknown whether Cx46 has a role in non-genetic cataract formation (i.e. aging and diabetes). Nitric oxide (NO) is a key element in non-genetic cataract formation and Cx46 hemichannels have been shown to be sensitive to NO. The molecular mechanisms of the effects of NO on Cx46 are unknown, but are likely to result from Cx46 S-nitrosation (also known as S-nitrosylation). In this work, we found that lens opacity was correlated with Cx46 S-nitrosation in an animal model of cataract. Consistent with this result, a NO donor increased Cx46 S-nitrosation and hemichannel opening in HLE-B3 cells (cell line derived from human lens epithelial cells). Mutagenesis studies point to the cysteine located in the fourth transmembrane helix (TM4; human C212, rat C218) as the NO sensor. Electrophysiological studies performed in Xenopus oocytes revealed that rat Cx46 hemichannels are sensitive to different NO donors, and that the presence of C218 is necessary to observe the NO donors' effects. Unexpectedly, gap junctions formed by Cx46 were insensitive to NO or the reducing agent dithiothreitol. We propose that increased hemichannel opening and/or changes in their electrophysiological properties of human Cx46 due to S-nitrosation of the cysteine in TM4 could be an important factor in cataract formation.

KEYWORDS:

Cataract; Connexins; Hemichannels; Nitric oxide; Redox regulation

PMID:
30797972
DOI:
10.1016/j.niox.2019.02.007

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