Calcineurin is downstream of the inositol 1,4,5-trisphosphate receptor in the apoptotic and cell growth pathways

Abstract

The inositol 1,4,5-trisphosphate receptor (IP3R) is a calcium (Ca2+) release channel found on the endoplasmic reticulum of virtually all types of cells. Human T lymphocytes (Jurkat) that are made deficient in IP3R do not generate Ca2+ signals in response to T cell receptor stimulation, fail to translocate the nuclear factor for activated T cells to the nucleus, and are remarkably resistant to induction of apoptosis with CD95 (Fas), dexamethasone, γ irradiation, and T cell receptor stimulation using anti-CD3 antibody. Expression of constitutively active calcineurin A in IP3R- deficient T cells restored nuclear factor for activated T cells translocation to the nucleus and dephosphorylation of Bad and rendered the cells sensitive to apoptotic inducers. Induction of apoptosis required both active calcineurin A (ΔCnA) and activation-dependent colocalization of CnA with its substrate. Thus, the Ca2+-dependent phosphatase calcineurin (CnA) is downstream of the IP3R in both the cell growth and apoptotic signaling pathways.