Connexin hemichannels in the lens

Beyer, Eric C.; Berthoud, Viviana M.

doi:10.3389/fphys.2014.00020

Cited by 77 publications

(65 citation statements)

References 106 publications

(146 reference statements)

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“…Pal et al found that incorporation of even a single mutant protein molecule into a gap junction in Xenopus oocytes inhibited channel function [29]. Studies of certain connexin mutants linked to congenital cataracts have implicated hemichannels with aberrant voltage-dependent gating or modulation by divalent cations in disease pathogenesis [25]. Further deletion analysis has shown that the fourth transmembrane domain (M4) and a membrane proximal region (codons 231-294) of the cytoplasmic domain are needed for transport from the endoplasmic reticulum and localization to the plasma membrane [30].…”

Section: Discussionmentioning

confidence: 97%

“…Gap junctions are membrane specializations that contain clusters of intercellular channels that are permeable to ions and small solutes, including ions (K+, Ca2+), nutrients, small metabolites (e.g. glucose), and second messengers (inositol triphosphate, cAMP, cGMP) (≤1 kDa) [25]. These functions play a critical role in lens metabolic homeostasis and maintenance of transparency of fibers within the ocular lens.…”

Section: Discussionmentioning

confidence: 99%

“…Each gap junction channel comprises two hemichannels called connexons, which dock in the extracellular space between adjacent cells. Each connexon comprises a hexamer of connexins, which is formed predominantly by three isoforms of connexins (Cx43, Cx46, and Cx50) [12,25]. Connexin proteins are membrane proteins containing four transmembrane domains (M1, M2, M3, and M4), two extracellular loops (E1 and E2), and three intracellular regions (the NH2-terminus, a cytoplasmic loop, and the COOH-terminus; Fig.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A novel Cx50 (GJA8) p.H277Y mutation associated with autosomal dominant congenital cataract identified with targeted next-generation sequencing

Chen

Sun

et al. 2015

Graefes Arch Clin Exp Ophthalmol

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A novel Cx50 (GJA8) p.H277Y mutation associated with autosomal dominant congenital cataract identified with targeted next-generation sequencing

Chen

Sun

et al. 2015

Graefes Arch Clin Exp Ophthalmol

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“…However, the required diffusion time would be too long to explain a response in epithelium that is detectable at 1 min. We also considered the possibility that because cells throughout the fiber mass as well as the epithelium are functionally coupled (Bassnett et al, 1994; Beyer and Berthoud, 2014; Mathias et al, 2007), depolarization caused by damage at the posterior pole might have an immediate influence on the remainder of the lens. However, a depolarization-mediated response is not consistent with the ability of HC067047 to prevent SFK response.…”

Section: Discussionmentioning

confidence: 99%

Damage to lens fiber cells causes TRPV4-dependent Src family kinase activation in the epithelium

Shahidullah

Mandal

Delamere

2015

Experimental Eye Research

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The bulk of the lens consists of tightly packed fiber cells. Because mature lens fibers lack mitochondria and other organelles, lens homeostasis relies on a monolayer of epithelial cells at the anterior surface. The detection of various signaling pathways in lens epithelial cells suggests they respond to stimuli that influence lens function. Focusing on Src Family Kinases (SFKs) and Transient Receptor Potential Vanilloid 4 (TRPV4), we tested whether the epithelium can sense and respond to an event that occurs in fiber mass. The pig lens was subjected to localized freeze-thaw (FT) damage to fibers at posterior pole then the lens was incubated for 1–10 min in Krebs solution at 37°C. Transient SFK activation in the epithelium was detectable at 1 min. Using a western blot approach, the ion channel TRPV4 was detected in the epithelium but was sparse or absent in fiber cells. Even though TRPV4 expression appears low at the actual site of FT damage to the fibers, SFK activation in the epithelium was suppressed in lenses subjected to FT damage then incubated with the TRPV4 antagonist HC067047 (10 μM). Na,K-ATPase activity was examined because previous studies report changes of Na,K-ATPase activity associated with SFK activation. Na,K-ATPase activity doubled in the epithelium removed from FT-damaged lenses and the response was prevented by HC067047 or the SFK inhibitor PP2 (10 μM). Similar changes were observed in response to fiber damage caused by injection of 5μl hyperosmotic NaCl or mannitol solution beneath the surface of the posterior pole. The findings point to a TRPV4-dependent mechanism that enables the epithelial cells to detect remote damage in the fiber mass and respond within minutes by activating SFK and increasing Na,K-ATPase activity. Because TRPV4 channels are mechanosensitive, we speculate they may be stimulated by swelling of the lens structure caused by damage to the fibers. Increased Na,K-ATPase activity gives the lens greater capacity to control ion concentrations in the fiber mass and the Na,K-ATPase response may reflect the critical contribution of the epithelium to lens ion homeostasis.

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“…Connexins form intercellular channels that facilitate the circulation of water, ions and solutes within the avascular lens (Mathias et al, 2010). They can also form “hemichannels” connecting the cytoplasm and extracellular space (Beyer and Berthoud, 2014). …”

Section: Introductionmentioning

confidence: 99%

Connexin23 deletion does not affect lens transparency

Berthoud

Minogue

Snabb

et al. 2016

Experimental Eye Research

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While connexin46 (Cx46) and connexin50 (Cx50) are crucial for maintaining lens transparency and growth, the contributions of a more recently identified lens fiber connexin, Cx23, are poorly understood. Therefore, we studied the consequences of absence of Cx23 in mouse lenses. Cx23-null mice were generated by homologous Cre recombination. Cx23 mRNA was abundantly expressed in wild type lenses, but not in Cx23-null lenses. The transparency and refractive properties of Cx23-null lenses were similar to wild type lenses when examined by darkfield microscopy. Neither the focusing ability nor the light scattering was altered in the Cx23-null lenses. While both Cx46 and Cx50 localized to appositional fiber cell membranes (as in wild type lenses), their levels were consistently (but not significantly) decreased in homozygous Cx23-null lenses. These results suggest that although Cx23 expression can influence the abundance of the co-expressed lens fiber connexins, heterozygous or homozygous expression of a Cx23-null allele does not alter lens transparency.

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Connexin hemichannels in the lens

Cited by 77 publications

References 106 publications

A novel Cx50 (GJA8) p.H277Y mutation associated with autosomal dominant congenital cataract identified with targeted next-generation sequencing

A novel Cx50 (GJA8) p.H277Y mutation associated with autosomal dominant congenital cataract identified with targeted next-generation sequencing

Damage to lens fiber cells causes TRPV4-dependent Src family kinase activation in the epithelium

Connexin23 deletion does not affect lens transparency

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