Regulation of the calmodulin-stimulated protein phosphatase, calcineurin.

The role of protein phosphatases in the regulation of cellular processes is now well established (1, 2). Calcineurin (also called protein phosphatase 2B), a major calmodulin-binding protein in brain and the only serine/threonine protein phosphatase under the control of Ca/calmodulin, plays a critical role in the coupling of Ca signals to cellular responses (3–6). Its stimulation by the multifunctional protein, calmodulin, ensures the coordinated regulation of its protein phosphatase activity with the activities of the many other enzymes, including a large number of protein kinases, under Ca and calmodulin control. Despite its special abundance in neural tissues, calcineurin is broadly distributed, and its structure is highly conserved from yeast to man (6). Its resistance to the endogenous phosphatase inhibitor 1 and inhibitor 2 and to the potent inhibitors of protein phosphatase 1 and 2A, okadaic acid, calyculin, and microcystin (1, 2) made it difficult to identify its functions until it was identified as the target of the immunosuppressive drugs, FK506 and cyclosporin A (CsA). Calcineurin was thus shown to play an essential role in T cell activation (7). The demonstration that FK506 and CsA, when bound to their respective binding proteins, FKBP12 and cyclophilin A, are specific inhibitors of calcineurin provided the tools needed to reveal its many other roles in the transduction of Ca signals (8). Its calmodulin dependence distinguishes it from two other known Ca-regulated protein phosphatases, the insulin-sensitive pyruvate dehydrogenase phosphatase of mitochondria (9) and a family of protein phosphatases homologous to the product of the Drosophila retinal degeneration C (rdgC) gene (10–12).