Akt2 inhibits the activation of NFAT in lymphocytes by modulating calcium release from intracellular stores

The engagement of antigen receptors on lymphocytes leads to the activation of phospholipase C-γ, the mobilization of intracellular calcium and the activation of the NFAT transcription factor. The coupling of antigen receptors to the activation of NFAT is modulated by numerous cellular effectors including phospho-inositide 3-kinase (PI3K), which is activated following receptor cross-linking. The activation of PI3K has both positive and negative effects on the receptor-mediated activation of NFAT. An increase in the level and activity of Akt2, a target of activated PI3K, potently inhibits the subsequent activation of NFAT. In contrast, an elevation in Akt1 has no effect on signaling. Signaling pathways operating both upstream and downstream of inositol 1,4,5-trisphosphate (IP3)-stimulated calcium release from intracellular stores are unaffected by Akt2. An increase in the level of Akt2 has no significant effect on the initial amplitude, but substantially reduces the duration of calcium mobilization. The ability of Akt2 to inhibit prolonged calcium mobilization is abrogated by the administration of a cell permeable peptide that blocks the interaction between Bcl-2 and the IP3 receptor. Thus, Akt2 is a negative regulator of NFAT activation through its ability to inhibit calcium mobilization from the ER. ► Akt negatively regulates the activation of NFAT through the B cell antigen receptor. ► Akt2, but not Akt1, inhibits antigen receptor-mediated activation of NFAT. ► Akt2 fails to block signaling upstream or downstream of calcium release from the ER. ► Akt2 inhibits sustained calcium release from the endoplasmic reticulum. ► Inhibition by is reversed by blocking Bcl-2 binding to the IP3 receptor.