Block of Lens and Neuronal Gap Junctions by Quinine

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DESCRIPTION: The lens is an avascular organ and therefore relies on a unique microcirculatory system to transport nutrients and metabolites to its core. Gap junction channels are important components of this microcirculation and thus maintenance of homeostasis and transparency of the lens is critically dependent on their presence. Three gap junction proteins (connexins) are expressed in the lens. They are Cx43, Cx46 and Cx50. Mice lacking Cx50 or Cx46 develop nuclear cataracts. In addition, the lenses of Cx50 knockout mice are smaller than normal, implying an early developmental defect. We have developed an additional tool to discriminate between the different connexins. A potent and specific blocker of Cx50 gap junction channels was identified. This drug blocks Cx50 channels with an IC50 value of ~ 1 uM; block of the other two gap junctions expressed in the lens, Cx43 and Cx46, occurs only at 15- and 75-fold higher concentrations respectively. This observation forms the basis of this proposal. The overall goals of this project is to use a pharmacological approach to provide an understanding of the role of Cx50 gap junctions and hemichannels in maintaining transparency of the lens and in controlling lens growth. Such a pharmacological approach will also serve to complement studies on genetically engineered mice.