Distinct tissue and cellular distribution of two major isoforms of calcineurin

The protein phosphatase calcineurin is known to be an essential intracellular signal transducer involved in the TCR-mediated signal transduction pathway and is the common target of the immunosuppressive drugs cyclosporin A (CsA) and FK506. The catalytic subunit of calcineurin exists in multiple isoforms, but their functional differences are not known. It has been assumed that the alpha isoform of calcineurin is the relevant isoform mediating TCR signaling. Recently, calcineurin alpha was knocked out in mice, but no defect in the TCR-mediated IL-2 production was observed, suggesting that another isoform of calcineurin mediates the TCR signal transduction pathway. We have generated specific polyclonal antibodies against the alpha and the beta2 isoforms of calcineurin and examined their distribution in murine tissues and immune cells by immunohistochemical staining and Western blot analysis. We found that the beta2 isoform of calcineurin is predominant in T and B lymphocytes as well as in thymus compared to the alpha isoform, suggesting that the beta2 isoform may play a key role in TCR signaling. Furthermore, we observed that the two isoforms exhibit distinct expression patterns in both kidney and thymus, indicating that the two isoforms of calcineurin have distinct cellular functions. Together, these findings raise the possibility that the nephrotoxicity associated with CsA and FK506 can be reduced by designing novel inhibitors of calcineurin that target specific isoforms of the enzyme.