CAIN, A NOVEL PHYSIOLOGICAL PROTEIN INHIBITOR OF CALCINEURIN

Calcineurin is a widely distributed protein phosphatase regulated by c alcium and calmodulin. It mediates the immunosuppressive actions of dr ugs such as cyclosporin and FK506, and has been implicated in a number of calcium-sensitive pathways in the nervous system, including regula tion of neurotransmitter release and modulation of long-term changes i n synaptic plasticity. Calcineurin associates physiologically with oth er proteins, including calmodulin, FKBP12 (FK506-binding protein), the ryanodine receptor, and the inositol 1,4,5-trisphosphate receptor. We now report the identification, molecular cloning, and functional char acterization of a novel protein, cain (ca lcineurin inhibitor), that i nteracts with and inhibits calcineurin. The full-length cain cDNA pred icts a 240-kDa protein with no significant homology to any known prote in. Cain associates with calcineurin both in vitro and in vivo, leadin g to a non-competitive inhibition of calcineurin activity. The putativ e calcineurin-binding domain of cain, a 38-amino acid region defined b y mutational analysis, is highly basic. Like calcineurin, cain has a p rominent neuronal expression and a wide tissue distribution. Cain's ex pression pattern in the brain closely resembles that of calcineurin, i ndicating a physiologic association between the two proteins.