摘要
Accumulating evidence indicates that the synaptic activation of N-methyl-o-aspartate receptors （NMDARs） has a neuroprotective effect on neurons. Our previous study demonstrated that APPL1 （adaptor protein containing pleckstrin homology domain, phosphotyrosine- binding domain, and leucine zipper motif） mediates the synaptic activity-dependent activation of PI3K-Akt signaling via coupling this pathway with NMDAR-PSD95 （postsynaptic density protein 95） complexes. However, the molecular mechanism underlying this process is still unknown. In the present study, we investigated the inter- action of APPL1 with PSD95 using co-immunocyto- chemical staining and western blotting. We found that the PDZ2 domain of PSD95 is a binding partner of APPL1. Furthermore, we identified serine 707 of APPL1, a pre- dicted phosphorylation site within the PDZ-binding motif at the C-terminus, as critical for the binding of APPL1 to PSD95, as well as for activation of the Akt signaling pathway during synaptic activity. This suggests that serine 707 of APPL1 is a potential phosphorylation site and may be involved in regulating the neuroprotective Akt signaling pathway that depends on synaptic NMDAR activity.
Accumulating evidence indicates that the synaptic activation of N-methyl-o-aspartate receptors （NMDARs） has a neuroprotective effect on neurons. Our previous study demonstrated that APPL1 （adaptor protein containing pleckstrin homology domain, phosphotyrosine- binding domain, and leucine zipper motif） mediates the synaptic activity-dependent activation of PI3K-Akt signaling via coupling this pathway with NMDAR-PSD95 （postsynaptic density protein 95） complexes. However, the molecular mechanism underlying this process is still unknown. In the present study, we investigated the inter- action of APPL1 with PSD95 using co-immunocyto- chemical staining and western blotting. We found that the PDZ2 domain of PSD95 is a binding partner of APPL1. Furthermore, we identified serine 707 of APPL1, a pre- dicted phosphorylation site within the PDZ-binding motif at the C-terminus, as critical for the binding of APPL1 to PSD95, as well as for activation of the Akt signaling pathway during synaptic activity. This suggests that serine 707 of APPL1 is a potential phosphorylation site and may be involved in regulating the neuroprotective Akt signaling pathway that depends on synaptic NMDAR activity.
基金
supported by grants from the National Natural Science Foundation of China(91232303,81221003,and 81561168)
