Abstract
Both connexin 50 (Cx50) and aquaporin 0 (AQP0) have important roles in lens development and homeostasis, and their mutations are associated with human congenital cataracts. We have previously shown that Cx50 directly interacts with AQP0. Here, we demonstrate the importance of the Cx50 intracellular loop (IL) domain in mediating the interaction with AQP0 in the lens in vivo. AQP0 significantly increased (~20-30%) the intercellular coupling and conductance of Cx50 gap junctions. However, this increase was not observed when the IL domain was replaced with those from other lens connexins. The Cx50-AQP0 interaction had no effect on Cx50 hemichannel function. A fusion protein containing three extracellular loop domains of AQP0 efficiently blocked the cell-to-cell adhesion of AQP0 and attenuated the stimulatory effect of AQP0 on Cx50 gap junction conductance. These data suggest that the specific interaction between Cx50 and AQP0 enhances the coupling of Cx50 gap junctions, but not hemichannels, through the cell adhesion function of AQP0. This result establishes a physiological role of AQP0 in the functional regulation of gap junction channels.
Highlights
As an avascular organ, the lens is formed by an anterior epithelial cell layer and highly differentiated fiber cells constituting the bulk of the lenticular mass
The connexin 50 (Cx50)–aquaporin 0 (AQP0) interaction enhances the ability of Cx50 to form functional gap junctions on the cell surface through the cell adhesion function of AQP0, but not hemichannels. These results suggest that AQP0 has a specific role in facilitating the function of gap junctions during early lens development, which is independent of hemichannel function
The intracellular loop (IL) domain of Cx50 facilitates the interaction with AQP0 in differentiating lens fibers We have previously shown that the IL domain of Cx50 directly interacts with the CT domain of AQP0 in vitro (Yu et al, 2005)
Summary
The lens is formed by an anterior epithelial cell layer and highly differentiated fiber cells constituting the bulk of the lenticular mass. Active epithelial cells at the lens equator start to differentiate and form new lens fibers, which gradually lose their intracellular nuclei and organelles during lens development and turn into mature lens fibers with accumulating high concentrations aquaporin 0 (AQP0) and soluble proteins known as crystallins. All connexins have four conserved transmembrane domains and two extracellular loop (EL) domains, whereas their intracellular loop (IL) domains and C-terminal (CT) domains are the most variable regions. Connexin 43 (Cx43) is mainly localized in the anterior epithelial cells and in the lens bow region along with Cx50; whereas Cx50 and Cx46 predominantly colocalize in the lens fibers and are able to form heteromeric connexons (Jiang and Goodenough, 1996). The physiological importance of lens gap junctions has been recognized in the past decade through the identification of connexin mutations that cause lens congenital cataracts in humans and the lens phenotypes displayed in connexindeficient mouse models (for reviews see Gerido and White, 2004; Gong et al, 2007)
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