FUNCTION OF FK506 BINDING-PROTEIN (FKBP) IN CHICK EMBRYONIC CARDIAC DEVELOPMENT

FK506 binding protein (BP) 12, an immunophilin of FK506-binding protei ns, is involved in intra-cellular signal transduction through the calc ineurin-nuclear factor pathway. FKBP12 is reported to be associated wi th the ryanodine-receptor and IP3 Ca2+ channels, and to regulate cell proliferation via binding transforming growth factor (TGF)-beta recept or and cyclin dependent kinase (CDK). To elucidate the function of FKB P12 in cardiac development, we analyzed the temporal profile and regul ation of FKBP12 expression in chick heart and in cultured cardiomyocyt es. FKBP12 is expressed in embryos as early as day 4 and is predominan tly associated with cardiomyocytes and osteo-chondrocytes. Tissue FKBP level in the heart increases with development. Immunohistochemically, the distribution and levels of FKBP12 appear to be related to sarco-e ndoplasmic reticulum Ca-ATPase 2 (SERCA2) but not to sarcomeric protei ns. In proliferating cells, FKBP12 expression correlates with cellular mitosis, but not with DNA synthesis. In earlier embryos (<day 8), sup pressing the activity of FKBP by FK506 administration is lethal, and i nduces cardiomegaly at later stages. In cultured cardiomyocytes, FK506 reduces the level of contractile proteins and inhibits cell prolifera tion. These results show that FKBP12 is enriched in cell types involve d in dynamic Ca handling, and is likely an important molecule for card iac development. FKBP12 most likely functions by affecting cellular Ca handling, since its effects are modified by modulators of Ca handling by sarcoplasmic reticulum.