Loss of fiber cell communication may contribute to the development of cataracts of many different etiologies

Abstract

The lens is an avascular organ that is supported by an internal circulation of water and solutes. This circulation is driven by ion pumps, channels and transporters in epithelial cells and by ion channels in fiber cells and is maintained by fiber-fiber and fiber-epithelial cell communication. Gap junctional intercellular channels formed of connexin46 and connexin50 are critical components of this circulation as demonstrated by studies of connexin null mice and connexin mutant mice. Moreover, connexin mutants are one of the most common causes of autosomal dominant congenital cataracts. However, alterations of the lens circulation and coupling between lens fiber cells are much more prevalent, beyond the connexin mutant lenses. Intercellular coupling and levels of connexins are decreased with aging. Gap junction-mediated intercellular communication decreases in mice expressing mutant forms of several different lens proteins and in some mouse models of lens protein damage. These observations suggest that disruption of ionic homeostasis due to reduction of the lens circulation is a common component of the development of many different types of cataracts. The decrease in the lens circulation often reflects low levels of lens fiber cell connexins and/or functional gap junction channels.

A crystallin mutant cataract with mineral deposits

“…Because mutations in other lens membrane and soluble proteins ( 27 ), including crystallins ( 28 , 29 ), can affect levels of lens fiber cell connexins, we determined the levels of Cx46 and Cx50 in the γC-crystallin mutant lenses by immunoblotting of lens homogenates. At 30 days of age, levels of Cx46 were significantly decreased to 20% (heterozygotes) and 11% (homozygotes), and levels of Cx50 were significantly decreased to 27% (heterozygotes) and 26% (homozygotes), compared to the levels in lenses from wild-type littermates ( Fig.…”

“…Gap junction–mediated fiber cell-to-fiber cell coupling plays a pivotal role in the circulation of ions, water, and molecules throughout the lens ( 30 ). It is reduced in several cataract mouse models with mutations in different genes, including those encoding Cx46 and Cx50 (reviewed in ( 27 )). In the lenses from mouse cataract models with reduced gap junction coupling and consequent alterations of the lens circulation, the gradients of ion concentrations and hydrostatic pressure are substantially affected (reviewed in ( 27 )).…”

“…It is reduced in several cataract mouse models with mutations in different genes, including those encoding Cx46 and Cx50 (reviewed in ( 27 )). In the lenses from mouse cataract models with reduced gap junction coupling and consequent alterations of the lens circulation, the gradients of ion concentrations and hydrostatic pressure are substantially affected (reviewed in ( 27 )). This alteration in the lens circulation (which also affects the gradient of Ca 2+ concentrations) results in the accumulation of Ca 2+ toward the center of the lens to levels that can become high enough to cause precipitation of Ca 2+ ions by interaction with the anions present in the tissue.…”

Connexin channels and hemichannels are modulated differently by charge reversal at residues forming the intracellular pocket

“…Cx46R33L and Cx50E162K have been linked to autosomal dominant cataracts [ 52 , 53 ]. Since the structure of the Cx46 and Cx50 hemichannels are highly similar [ 6 , 7 ], our current results suggest that either of these mutations would cause a significant decrease in gap junctional coupling between lens fiber cells, which would impair the circulation of ions and fluid through the organ and alter homeostasis [ 54 , 55 ]. In addition, the E162K substitution in Cx50 would increase release of ATP, even in the presence of physiological concentrations of extracellular Ca 2+ , which may lead to its intracellular depletion.…”

Diversity in connexin biology

“…However, models have been proposed where mechanosensitive hemichannels accommodate a steady-state fluid equilibrium and pathways for the influx of calcium and sodium, and the efflux of potassium ( 37 , 38 ) required for normal lens function and maintenance of transparency. Amplified hemichannel activity, as seen for some diseased-linked Cx46 and Cx50 gene mutations ( 39 ), may lead to ATP and GSH leaking from lens cells harboring these mutants culminating in cytotoxicity and/or cataracts. In another example, mechanosensitive hemichannels are found in bone osteocytes, where they appear to play a role in bone remodeling and plasticity through their regulated release of ATP, NAD + , and prostaglandin E 2 ( 40 ).…”