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

Abstract

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.

Levels and Modifications of Both Lens Fiber Cell Connexins Are Affected in Connexin Mutant Mice

“…Our alkaline phosphatase experiments also showed the presence of immunoreactive Cx46 with a modification that was not sensitive to alkaline phosphatase treatment. This may not be surprising since other modifications (including acetylation, nitrosylation, and carbamylation) have been detected in Cx46 (reviewed in Retamal and Altenberg [ 25 ]). In Cx43, some phosphates are removed by acid phosphatase [ 26 ].…”

Gap junction Delta-2b (gjd2b/Cx35.1) depletion causes hyperopia and visual-motor deficiencies in the zebrafish

“…We conclude that the moderate downregulation detected in our fish model was insufficient to cause a similar phenotype. However, in mammalians and humans, the expression of mutants of the orthologous gene Cx50 is associated with cataract formation, smaller lenses, and eyes, indicating the importance of gap junctions in the maintenance of lens fiber homeostasis in mammals (Beyer and Berthoud, 2014;Berthoud et al, 2020;Retamal and Altenberg, 2022). Hirata et al (2012) showed that morpholino-based depletion of gja2/Cx39.9 in the zebrafish does not affect the locomotory behavior but caused abnormal thigmotaxis and changes to muscle contraction (Hirata et al, 2012).…”

Diversity in connexin biology

“…While it is not our intent here to cover the breadth of evidence that supports a key role for connexin hemichannels, we would be remiss not to give a couple of examples. The first is in the lens where Cx46 hemichannels play a critical role in maintaining lens homeostasis ( 36 , 37 , 38 ). The precise roles that Cx43, Cx46, or Cx50 hemichannels play in normal human lens remains somewhat elusive.…”