Considerable evidence suggests that synaptic function is severely compromised in Alzheimer's disease and other neurodegenerative diseases, leading to cognitive defects even during the early stages of these diseases. It is well known that protein phosphatase-1 (PP1) plays a critical role in synaptic function. However, our preliminary data indicates that there are at least two synaptic PP1 populations which can exert differential functions on synaptic transmission. Our immediate goal is to elucidate the differential targeting and signaling mechanisms underlying these two synaptic PP1 populations. Our longer-term goal is to apply this knowledge in understanding how impairment of PP1 signaling in synaptic function can be prevented in diseases. Our newly acquired preliminary data suggest that two distinct pools of PP1, probably targeted respectively by neurabin and spinophilin, have opposite functions in synaptic transmission and play differential roles in long term depression (LTD). In this proposal, we hypothesize that neurabin and spinophilin can exert their opposite effects on basal synaptic transmission (Aim 1) through micro-targeting their cargoes (PP1) to distinct micro-compartments within synapses, acting on different substrates, i.e, Ser657 on PKC? (and indirectly on Ser880 on GluR2) and Ser831 on GluR1, respectively. In response to LTD stimulus (Aim2), we propose to test our hypothesis that neurabin will traffic to PSD fraction to dephosphorylate GSK3?, leading to synaptic depression while spinophilin does not play a role in this process. Critical domains on neurabin and spinophilin mediating their distinct effects will be elucidated in these two aims by a combination of electrophysiological recording and the state-of-the-art molecular replacement approach.
In Aim3, we will hypothesize that neurabin, but not spinophilin, plays a negative role in LTP expression. We propose to determine the phosphorylation mechanism on neurabin by which LTP stimulus uses to overcome the inhibitory effects of Nrb/PP1 complex for normal LTP to occur. Finally we will also test the hypotheses that Nrb/PP1 modifies CaMKII and/or GSK3? for its inhibitory function in LTP. The results obtained from these studies will provide a better understanding of biological mechanisms that (1) regulate PP1 interaction with different binding proteins for differential substrate specificity, (2) structural basis for the critical functions of neurabin and spinophilin in synaptic functions;and (3) provide insights into therapeutic cures for the cognitive defects in patients with neuro-degenerative diseases.
Considerable evidence suggests that synaptic function is severely compromised in Alzheimer's disease and other neurodegenerative diseases, leading to cognitive defects even during the early stages of these diseases. Our proposed study is to examine the phosphatases signaling mechanisms underlying synaptic functions. The results obtained from these studies will provide molecular insights into therapeutic cures for the cognitive defects in patients with neuro-degenerative diseases.
|Siddoway, Benjamin; Hou, Hailong; Yang, Hongtian et al. (2014) Synaptic activity bidirectionally regulates a novel sequence-specific S-Q phosphoproteome in neurons. J Neurochem 128:841-51|
|Siddoway, Benjamin; Hou, Hailong; Xia, Houhui (2014) Molecular mechanisms of homeostatic synaptic downscaling. Neuropharmacology 78:38-44|
|Hou, Hailong; Chávez, Andrés E; Wang, Chih-Chieh et al. (2014) The Rac1 inhibitor NSC23766 suppresses CREB signaling by targeting NMDA receptor function. J Neurosci 34:14006-12|
|Hou, Hailong; Sun, Lu; Siddoway, Benjamin A et al. (2013) Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5. J Cell Biol 203:521-35|
|Siddoway, Benjamin A; Altimimi, Haider F; Hou, Hailong et al. (2013) An essential role for inhibitor-2 regulation of protein phosphatase-1 in synaptic scaling. J Neurosci 33:11206-11|
|Dong, Chunmin; Yang, Lingling; Zhang, Xiaoping et al. (2010) Rab8 interacts with distinct motifs in alpha2B- and beta2-adrenergic receptors and differentially modulates their transport. J Biol Chem 285:20369-80|