Mechanosensitive collaboration between integrins and connexins allows nutrient and antioxidant transport into the lens

Abstract

The delivery of glucose and antioxidants is vital to maintain homeostasis and lens transparency. Here, we report a new mechanism whereby mechanically activated connexin (Cx) hemichannels serve as a transport portal for delivering glucose and glutathione (GSH). Integrin α6β1 in outer cortical lens fiber activated by fluid flow shear stress (FFSS) induced opening of hemichannels. Inhibition of α6 activation prevented hemichannel opening as well as glucose and GSH uptake. The activation of integrin β1, a heterodimeric partner of α6 in the absence of FFSS, increased Cx50 hemichannel opening. Hemichannel activation by FFSS depended on the interaction of integrin α6 and Cx50 C-terminal domain. Moreover, hemichannels in nuclear fiber were unresponsive owing to Cx50 truncation. Taken together, these results show that mechanically activated α6β1 integrin in outer cortical lens fibers leads to opening of hemichannels, which transport glucose and GSH into cortical lens fibers. This study unveils a new transport mechanism that maintains metabolic and antioxidative function of the lens.

Aging-dependent loss of GAP junction proteins Cx46 and Cx50 in the fiber cells of human and mouse lenses accounts for the diminished coupling conductance

“…Gap junction proteins play an important role in lens homeostasis and transparency [ 3 – 5 , 11 – 25 , 65 – 67 ]. They are responsible for transporting small molecular nutrients and metabolites [ 11 – 18 , 24 – 25 ].…”

“…Gap junction proteins play an important role in lens homeostasis and transparency [ 3 – 5 , 11 – 25 , 65 – 67 ]. They are responsible for transporting small molecular nutrients and metabolites [ 11 – 18 , 24 – 25 ]. More recently, Liu et al [ 21 ] elegantly demonstrated that these gap junction proteins are also capable of delivering antioxidants and maintaining the redox status of the ocular lens.…”

“…Cleavages of these two connexin proteins were mediated by the enzymatic action of calpain and other proteases or non-enzymatical reaction. Truncation-caused decrease in coupling conductance led to changes in transport of ions and important metabolites in the lens, for example, antioxidant cannot diffuse from the outer cortex to the fiber cells, resulting change in the glutathione redox state in the inner lens [ 25 ]. In addition, caspase-1/-3-mediated truncations at the C-terminal (Glu-368 and Asp-379) of chicken lens Cx50 also cause decrease in gap junction coupling [ 68 ].…”

“…Both hemichannels and full gap junction channels play an important role in maintaining lens transparency [ 3 , 11 – 25 ]. These gap junction channels are capable of transporting small molecular nutrients and metabolites [ 23 – 25 ]. More recently, it was found that these channels are also responsible for the delivery of antioxidants [ 25 ].…”

“…These gap junction channels are capable of transporting small molecular nutrients and metabolites [ 23 – 25 ]. More recently, it was found that these channels are also responsible for the delivery of antioxidants [ 25 ].…”