Cyclosporin A binding to calmodulin: a possible site of action on T lymphocytes.
Cyclosporin A, a potent immunosuppressive agent, has been widely used to treat patients with solid organ transplants. Although its precise mechanism of action is unknown, it appears to inhibit subsets of T lymphocytes at an early stage in cell activation. Fluorescent, fully active derivatives of cyclosporin A and calmodulin, a protein that binds calcium and is therefore essential to normal cell function, were utilized to demonstrate that cyclosporin A binds to calmodulin. Flow cytometry showed that the calmodulin inhibitors R24571 and W-7 competitively inhibited binding of cyclosporin A to cloned T lymphocytes. Cyclosporin A inhibited the calmodulin-dependent activation of phosphodiesterase in a dose-dependent manner. Binding of cyclosporin A to calmodulin may prevent the latter's role in the activation of the second messengers and enzymes required for effective cell proliferation and function in the immune response.
D001667:Binding, Competitive; D002147:Calmodulin / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D003524:Cyclosporins / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D007093:Imidazoles / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D019696:Peptidylprolyl Isomerase; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
D002147:Calmodulin; D002352:Carrier Proteins; D003524:Cyclosporins; D007093:Imidazoles; D013449:Sulfonamides; C031938:calmidazolium; C017967:W 7; D019696:Peptidylprolyl Isomerase