Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C (PKC) plays an important role in regulating cell growth. In the cornea, alpha-PKC activity increases during wound-healing. This activation of PKC will result in the increased phosphorylation of specific PKC substrates. In this study, several PKC substrates of relative low molecular weight were identified and characterized in cytosol and membrane preparations obtained from rabbit corneal epithelium before and during wound-healing. Corneal epithelium proteins were phosphorylated by endogenous PKC and by alpha-PKC isolated from rabbit brain, and then analysed using SDS-PAGE. In cytosol, PKC substrates with apparent molecular weights of 20, 25, 30, 35, 50 and 55 kDa were phosphorylated by PKC. The phosphorylation of the substrates increased 3 and 7 days after total de-epithelialization, due to the increase in alpha-PKC activity after wounding. However, when brain alpha-PKC was used as the exogenous source of PKC, there was a protein concentration-related decrease in the phosphorylation of corneal epithelium substrate after injury. This decreased phosphorylation of PKC substrates was inhibited by okadaic acid, a specific phosphatase inhibitor. The results suggest that an activated protein phosphatase takes part in controling the phosphorylation of PKC substrates during wound-healing. In the membrane fraction, a 60 kDa protein was phosphorylated by alpha-, beta- and gamma-PKC isoenzymes and was identified by Western blot as growth associated protein-43 (GAP-43), a protein kinase C substrate involved in axon regeneration. GAP-43 concentration increased 3 and 7 days after wounding as did its phosphorylation by alpha-PKC. These findings suggest a role for the protein in the innervation process in corneal epithelium after injury.
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PMID:Protein kinase C substrates in corneal epithelium during wound healing: the phosphorylation of growth associated protein-43 (GAP-43). 854 86

The role of Na(+)-K(+)-2Cl- cotransport in ion and fluid transport of the corneal endothelium was examined by measuring changes in corneal hydration and uptake of 86Rb by the endothelial cell layer. Isolated, intact rabbit corneas maintain normal hydration when they are superfused at the endothelial surface with bicarbonate (HCO3-)-Ringer solutions as a result of equilibrium between active ion and fluid transport out of the stromal tissue and leak of fluid into stromal tissue from the aqueous humor. Furosemide and bumetanide did not alter this equilibrium when they were added to the superfusion medium. Uptake of 86Rb by the endothelium of the incubated cornea was increased 25% by bumetanide, but uptake in the presence of ouabain (70% less than that of controls) was not changed by bumetanide. In Na(+)-free medium, uptake of 86Rb was reduced by 58%, but it was unchanged in Cl(-)-free medium. Calyculin A, a protein phosphatase inhibitor and activator of Na(+)-K(+)-Cl- cotransport, was without effect on 86Rb uptake. Hypertonicity (345 mosmol/kg) increased uptake slightly, whereas hypotonicity (226 mosmol/kg) caused a 33% decrease. Neither of these changes was significantly different when bumetanide was present in the media. It is concluded that Na(+)-K(+)-2Cl- cotransporter activity is not exhibited by the in situ corneal endothelium and does not play a role in the ion and fluid transport of this cell layer. Its presence in cultured endothelial cells may reflect the reported importance of this protein in growth, proliferation, and differentiation.
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PMID:Fluid and ion transport in corneal endothelium: insensitivity to modulators of Na(+)-K(+)-2Cl- cotransport. 937 32

The immune privileged nature of the cornea contributes to the favourable outcome in corneal grafts. However, preventive measures are necessary to reduce allograft rejection particular in "high-risk" cases. Although corticosteroids are still a major component of our immunopharmacological armentarium, they might be supplemented by other more specific immunomodulating agents. The spectrum includes agents such as azathioprin, methotrexate or more specific calcineurin inhibitors affecting T-cells (cyclosporin A, FK506) and highly selective monoclonal antibodies directed against T-cell subpopulations and other targets. In order to better evaluate the risks and benefit of these agents, the properties of established and forthcoming agents are presented. In addition, this review attempts to address some new concepts of tolerance induction following penetrating keratoplasty.
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PMID:[Immunomodulation in penetrating keratoplasty. Current status and perspectives]. 1470 16

Calcineurin inhibitors (CNIs) are potent immunosuppressants that reversibly inhibit T-cell proliferation and prevent the release of pro-inflammatory cytokines by blocking the activity of calcineurin, a ubiquitous enzyme that is found in cell cytoplasm. CNIs can be highly effective in immune-mediated ophthalmic diseases such as uveitis, dry eye syndrome and inflammatory blepharitis, as well as for the prevention of rejection in corneal transplants. ISA-247/LX-211 is a novel CNI that is in Phase III clinical development for the treatment of various forms of non-infectious uveitis. ISA-247/LX-211 is a rationally designed analog of ciclosporin A that exhibits more predictable pharmacokinetic and pharmacodynamic properties and a 4-fold greater calcineurin inhibition than its parent compound, ciclosporin A. ISA-247/LX-211 has been observed to be effective, well-tolerated, and safe in early clinical trials, exhibiting a much wider therapeutic window compared with classic CNIs, such as ciclosporin A and tacrolimus. An alternative approach to widening the therapeutic window for the therapy of ophthalmic disorders lies in local delivery of CNIs through polymeric implants that release the drug over long periods of time. The silicone matrix episcleral implant LX-201 is in Phase III development at present for the prevention of rejection in high-risk cornea transplantation.
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PMID:Next-generation calcineurin inhibitors for ophthalmic indications. 1792 18

Since its initial discovery as Ca(2+)/calmodulin (CaM)-dependent serine/threonine protein phosphatase, calcineurin (CaN) has been extensively studied in many mammalian tissues. CaN has been shown to be involved in various biological and Ca(2+)-dependent signal transduction pathways. Over the last decade, our laboratory has been interested and has carried out numerous experiments on this specific protein phosphatase. While, a lot of research has been performed studying CaN's involvement in ischemia, the immune system, and various mammalian tissues, not much is known about the potential role of CaN in various eye diseases. This review focuses on the studies that have been carried out in our laboratory on CaN, and specifically CaN's involvement in the eye. We demonstrated that CaN is localized in various eye tissues (cornea, iris, ciliary body, vitreous body, retina, choroid, sclera, and optic nerve) and that both its protein expression and activity were observed in high amounts in the retina, optic nerve and cornea. Recently, we have cloned and characterized the CaN A and B subunits in the bovine retina. These initial findings suggest that CaN may play a potential role in visual transduction and various ocular diseases, including cancer.
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PMID:Potential role of calcineurin in pathogenic conditions. 1996 49