July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Mechanical-sensitive hemichannels regulated by integrins mediates the delivery of glucose and glutathione into lens fiber cells
Author Affiliations & Notes
  • Jie Liu
    Biochemistry, university of Texas health science center at San antonio, San Antonio, Texas, United States
  • Manuel Riquelme
    Biochemistry, university of Texas health science center at San antonio, San Antonio, Texas, United States
  • Zhen Li
    Biochemistry, university of Texas health science center at San antonio, San Antonio, Texas, United States
  • Sumin Gu
    Biochemistry, university of Texas health science center at San antonio, San Antonio, Texas, United States
  • Jean X Jiang
    Biochemistry, university of Texas health science center at San antonio, San Antonio, Texas, United States
  • Footnotes
    Commercial Relationships   Jie Liu, None; Manuel Riquelme, None; Zhen Li, None; Sumin Gu, None; Jean Jiang, None
  • Footnotes
    Support  NIH Grant EY012085
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4794. doi:
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    • Get Citation

      Jie Liu, Manuel Riquelme, Zhen Li, Sumin Gu, Jean X Jiang; Mechanical-sensitive hemichannels regulated by integrins mediates the delivery of glucose and glutathione into lens fiber cells. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4794.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : How microcirculation of fluid delivers nutrients and antioxidants to the lens fiber cells to maintain lens transparency remains obscure. We hypothesize that Integrin, acting as a mechanosensory senor, mediates connexin hemichannel opening, leading to transport of glutathione and glucose into lens fiber cells.

Methods : In this study, fluid flow shear stress (FFSS) was employed to mimics mechanical loading introduced by microcirculation of fluid. The connexin (Cx) hemichannel activity was determined using dye uptake assay and transport of glucose and GSH into the cell and lens was performed by glucose and GSH uptake assays and flow cytometry. The relationship between integrin α6 and Cx50 was investigated by co-localization with immunofluorescence and protein interaction via co-immonuprecipitation assay. Truncated Cx50 construct was generated to mimic Cx truncation in the nuclear fibers and was expressed through recombinant RCAS(A) expression approach.

Results : Our data showed that Cx50 hemichannels in the lens fibers were activated by FFSS. The activation of these hemichannels mediated the uptake of extracellular glucose and GSH. Furthermore, we found that Integrin α6 was distributed mainly in the outer lens fibers and co-localized with Cx50. The co-immonuprecipitation assay showed that integrin α6 interacted with Cx50 and this interaction was increased by mechanical loading. Inhibition of integrin α6 activation by a blocking antibody prevented hemichannel opening as well as glucose and GSH uptake induced by FFSS. Consistently, activating antibody against integrin β1, an integrin heterodimeric partner of α6 similarly increased the hemichannel opening, and glucose and GSH uptake. However, the Cx50 368T truncation mutant which was cleaved at C-terminus of Cx50, a natural truncated form of Cx50 located in the mature lens fiber cells, failed to interact with integrin α6 and was unresponsive to FFSS.

Conclusions : The data suggest that during microcirculation, α6β1 integrin in cortical fibers is likely to be activated by mechanical stimulation via fluid flow shear stress. Through their interaction with α6β1 integrin, Cx50 hemichannels are activated, which mediates the transport of deliver glucose and GSH into cortical lens fibers to meet metabolic needs and protect lens from oxidative damages, sequentially maintaining lens transparency and homeostasis.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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