DISTINCT TISSUE AND CELLULAR-DISTRIBUTION OF 2 MAJOR ISOFORMS OF CALCINEURIN

The protein phosphatase calcineurin is known to be an essential intrac ellular signal transducer involved in the TCR-mediated signal transduc tion pathway and is the common target of the immunosuppressive drugs c yclosporin A (CsA) and FK506. The catalytic subunit of calcineurin exi sts in multiple isoforms, but their functional differences are not kno wn. It has been assumed that the alpha isoform of calcineurin is the r elevant isoform mediating TCR signaling, Recently, calcineurin alpha w as knocked out in mice, but no defect in the TCR-mediated IL-2 product ion was observed, suggesting that another isoform of calcineurin media tes the TCR signal transduction pathway. We have generated specific po lyclonal antibodies against the a and the beta 2 isoforms of calcineur in and examined their distribution in murine tissues and immune cells by immunohistochemical staining and Western blot analysis. We found th at the beta 2 isoform of calcineurin is predominant in T and B lymphoc ytes as well as in thymus compared to the cc isoform, suggesting that the beta 2 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 calcin eurin 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 caldineurin that targ et specific isoforms of the enzyme. (C) 1997 Published by Elsevier Sci ence Ltd.