Ca2+ and cyclic nucleotides are important regulators of cell activity in many systems. However, we know rather little of the role of these components in the lens. Based on our early work, these second messengers appear to play an important role in regulating several lens membrane proteins. In particular, our studies have focused on the 18 kDa integral lens membrane protein which is the major membrane substrate for cAMP- dependent protein kinase (cAMP-PK), and is also likely the major lens membrane receptor for calmodulin. The goal of this project is to define the role of this protein that has now been immunolocalized to lens junctional regions where it could either regulate, or possibly effect, intercellular communication. This project will also define the roles of the enzymes and substrates mediating the actions of cAMP and Ca2+ in non-junctional regions of the lens membrane where they likely regulate plasma membrane enzymes or ion pumps. The action of cAMP in regulating lens membrane function will be defined in five experimental approaches: (a) to characterize and localize adenylate cyclase in the lens plasma membrane, (b) to determine the role of peripheral membrane proteins in regulating the protein kinase-catalyzed phosphorylation of lens membrane proteins, (c) to analyze the membrane organization and partial sequence of the 18 kDa membrane component; its developmental appearance, regional distribution in the lens, and similarity to human junctional components will be examined, (d) to address whether antibodies to this protein can inhibit lens cell coupling, (e) to characterize the protein phosphatase activity in the lens. The action of Ca2+ in regulating lens cell function will be defined in three experimental approaches: (a) to immunolocalize the 61 kDa major calmodulin-binding component in buffer-washed membranes, (b) to define whether the 18 kDa cAMP-PK substrate is also the major calmodulin binding component in urea-washed lens membranes, (c) to characterize the ion pumps, carriers and channels that regulate intracellular Ca2+ levels in the lens. Many manifestations of cataracts are exaggerations of changes found in the aging lens. By defining the role of some of the functionally important lens membrane proteins, it is anticipated that this project will lead to an improved understanding of lens fiber regulation, and thus a better basis for interpreting the nature of cataract formation.
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