PT - JOURNAL ARTICLE AU - D Zhu AU - M E Cardenas AU - J Heitman TI - Calcineurin mutants render T lymphocytes resistant to cyclosporin A. DP - 1996 Sep 01 TA - Molecular Pharmacology PG - 506--511 VI - 50 IP - 3 4099 - http://molpharm.aspetjournals.org/content/50/3/506.short 4100 - http://molpharm.aspetjournals.org/content/50/3/506.full SO - Mol Pharmacol1996 Sep 01; 50 AB - The immunosuppressants cyclosporin A (CsA) and FK506 have been widely used to prevent and treat graft rejection after human organ and tissue transplantations. CsA and FK506 associate with intracellular binding proteins (i.e., CsA with cyclophilin A and FK506 with FKBP12) to form protein/drug complexes that suppress the immune system by preventing activation of T cells in response to antigen presentation. The common target of CsA and FK506 is calcineurin, a Ca2+/calmodulin-regulated, serine/threonine-specific protein phosphatase that regulates the nuclear import of a transcription factor, NF-AT, required for expression of T cell activation genes. In previous studies, we identified calcineurin mutations that block binding by the cyclophilin A/CsA or FKBP12/FK506 complexes and thereby render yeast cells resistant to the antifungal effects of CsA or FK506. In this report, we demonstrate that the corresponding mutations in murine calcineurin render the T cell receptor signal transduction cascade CsA resistant in human Jurkat T cells. Our findings support the recently determined calcineurin X-ray crystal structure, provide evidence that calcineurin is the only CsA-sensitive component limiting signaling from the T cell receptor to the nucleus, and suggest a means to render cells and tissues resistant to the toxic side effects of CsA and FK506.