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The RCAN1 protein (previously called calcipressin 1 or MCIP1) binds to calcineurin, a serine/threonine phosphatase (PP2B), and inhibits its activity. Here we demonstrate that regulated overexpression of an RCAN1transgene (this gene was previously called DSCR1 or Adapt78) also stimulates expression of the GSK-3β kinase, which can antagonize the action of calcineurin. We also show that GSK-3β is regulated by RCAN1 at a post-transcriptional level. In humans, high RCAN1 expression is found in the brain, where at least two mRNA isoforms have been reported. Therefore, we further investigated expression of the various RCAN1 isoforms, resulting from differential splicing and alternative promotors in human brain. We detected at least three distinct RCAN1s: RCAN1-1 Short at 31 kDa (RCAN1-1S), RCAN1-1 Long at 38 kDa (RCAN1-1 L), and RCAN1-4. Furthermore, the levels of RCAN1-1S, but not RCAN1-1 L or RCAN1-4 correlated with the levels of GSK-3β. This suggests that RCAN1-1S might induce production of GSK-3β in vivo. While RCAN1s can regulate calcineurin and GSK-3β, it has also been shown that calcineurin and GSK-3β can regulate RCAN1s. Here we propose a new model (incorporating all these findings) in which cells maintain an equilibrium between RCAN1s, calcineurin, and GSK-3β. [ABSTRACT FROM AUTHOR]