The nuclear localization and transcriptional activity of FoxO3a is negatively controlled by AKT mediated phosphorylation. Consistent with this we discovered that IGF 1 avoided the potassium deprivation induced decrease in AKT activity, FoxO3a dephosphorylation and attenuated Puma induction. Interestingly, we found that inhibition of order Dovitinib both JNK or GSK3b also inhibited FoxO3a dephosphorylation/activation. These results were surprising given that GSK3b is activated downstream of AKT and that JNK signaling doesn’t appear to influence AKT activity in this context. This means that JNK and GSK3b can manage FoxO3a phosphorylation by an indirect mechanism or via an AKT independent mechanism probably by regulating the activity of the phosphatase involved with FoxO3a dephosphorylation. Although JNK and GSK3b were found to affect FoxO3a activation we can not exclude the possibility that they may also control other transcription factors associated with Puma induction. An applicant factor downstream of GSK3b is nuclear factor of activated T cells which includes demonstrated an ability to be phosphorylated by GSK3b resulting in its export from Messenger RNA (mRNA) the nucleus and promotion of survival in CGNs. In cases like this NFAT may become a repressor of Puma transcription that will be removed upon GSK3b activation. Equally, beta catenin might be working to curb Puma induction until inactivated by GSK3b. Phosphorylation of beta catenin by GSK3b causes its translocation out of the nucleus and targets it for destruction and inhibition of this phosphorylation event has been connected with neuronal survival. Finally, there are several downstream targets of the JNK pathway that could control Puma expression natural product libraries following JNK activation, these generally include h Jun, activating transcription factor 2 and activating transcription factor 3. A primary downstream goal of JNK, c Jun has been found to be up-regulated in trophic factor deprived neurons and ectopic expression of dominating negative c Jun was found to protect against cell death. The JNK regulated transcription factors ATF2 and ATF3 are also induced in a reaction to potassium deprivation and it has been noted that knockdown or inhibition of those factors can protect neurons against apoptosis. It’s significant the Puma promoter contains putative AP1 binding sites which are the known target sequence for all three of these transcription factors, suggesting a possible function for these factors in Puma induction. Interestingly, a current study implicated c Jun in the regulation of Puma term in fatty acid induced apoptosis of hepatocytes, even though the AP 1 binding site identified in this study does not look like conserved. It is uncertain whether or not they may play a role in Puma upregulation in this context and is currently under investigation while these transcription factors have been implicated in neuronal apoptosis. In conclusion, we have delineated an integral process involved in the regulation of apoptosis induced by potassium deprivation in CGNs.