Abstract: There are a growing number of studies identifying secretin as a neuroprotective factor. Consistently, our previous data showed that neuronal apoptosis considerably increased in the developing cerebellum from secretin knockout (Sct-/-) mice. However, the underlying mechanisms remained poorly understood. Extracellular signal-regulated protein kinase (ERK) and AKT signalling pathways are known for the regulation of apoptosis. Additionally, these two pathways could activate cAMP-response-element-binding protein (CREB), which has been shown to promote cell survival. Therefore, their phosphorylation levels in the cerebellum were compared between Sct-/- and WT mice. The basal levels of phosphor-ERK1/2 (pERK1/2) and phosphor-CREB (pCREB) showed a significant decrease in Sct-/- mice, but not phosphor-AKT (pAKT). The cerebellar slices obtained from Sct-/- displayed a dose-dependent increase of pERK1/2 and pCREB, but not pAKT, in response to graded concentrations of secretin peptide and the impaired phosphorylation of ERK1/2 and CREB in Sct-/- cerebellar slices was able to be recovered by the treatment of secretin compared with WT, suggesting the involvement of ERK1/2 and CREB. Specific inhibitors were applied for further confirmation. Secretin failed to reduce the level of activated Caspase-3 when either ERK1/2 or CREB was inhibited, revealing that ERK1/2 and CREB was required for secretins neuroprotective function. Our results clearly provide evidence that ERK1/2 and CREB play a role in mediating the anti-apoptotic function of secretin.
20 - 23 May 2017
European Society of Endocrinology