Abstract

NMDA receptors play critical roles in the regulation of synaptic plasticity, neuronal development and several neurological and psychiatric diseases. Studies in the last ten years have shown that NMDA receptors bind to the PSD95/SAP90 family of adaptor protein to form a large macromolecular signaling complex. The PSD95/SAP90 protein family appears to play a critical role in the in the coupling of NMDA receptors to downstream signal transduction pathways and in the synaptic targeting of NMDA and AMPA receptors. In this research proposal we plan to study the structure, function and regulation of the NMDA receptor macromolecular signaling complex and the role of this complex in synaptic transmission and plasticity. Firstly, studies in our laboratory have shown that dynamic phosphorylation of the NMDA receptor by casein kinase II disrupts NMDA receptor binding to the PSD95/SAP90 protein and thus may play a critical role in the regulation of NMDA receptor signaling. We plan to study the regulation of this phosphorylation and examine its effect on NMDA receptor function and downstream signaling. Secondly, we previously showed that SynGAP, a synapse-specific RasGAP directly interacts with SAP102 and PSD95/SAP90 and that this interaction is important for regulation of synaptic transmission. We will further investigate the regulation of SynGAP and its role in Ras signaling at the molecular level using neurons transfected with wildtype and mutant forms of SynGAP and with SynGAP knock-out mice. Finally, we will identify and characterize synaptic substrates for MAP kinase signaling pathway enzymes including the ERK, RSK, JNK and p38 protein kinases. These kinases, which are all present in the NMDA receptor-signaling complex, play critical roles in the regulation of synaptic transmission and plasticity. However, the synaptic substrates for these kinases are largely unknown. The role of phosphorylation of MAP kinase synaptic substrates in modulating synaptic function will be determined. These studies will investigate the function of the NMDA receptor protein signaling complex at three different levels and will help elucidate the function of this complex in excitatory synaptic function and its potential role in neurological and psychiatric diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH064856-10
Application #
8068646
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2001-12-13
Project End
2012-05-31
Budget Start
2011-05-01
Budget End
2012-05-31
Support Year
10
Fiscal Year
2011
Total Cost
$345,015
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Lim, Chae-Seok; Kang, Xi; Mirabella, Vincent et al. (2017) BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method. Genes Dev 31:537-552
Gu, Yi; Chiu, Shu-Ling; Liu, Bian et al. (2016) Differential vesicular sorting of AMPA and GABAA receptors. Proc Natl Acad Sci U S A 113:E922-31
Gu, Yi; Huganir, Richard L (2016) Identification of the SNARE complex mediating the exocytosis of NMDA receptors. Proc Natl Acad Sci U S A 113:12280-12285
Araki, Yoichi; Zeng, Menglong; Zhang, Mingjie et al. (2015) Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP. Neuron 85:173-189
Thomas, Gareth M; Hayashi, Takashi; Chiu, Shu-Ling et al. (2012) Palmitoylation by DHHC5/8 targets GRIP1 to dendritic endosomes to regulate AMPA-R trafficking. Neuron 73:482-96
Makuch, Lauren; Volk, Lenora; Anggono, Victor et al. (2011) Regulation of AMPA receptor function by the human memory-associated gene KIBRA. Neuron 71:1022-9
Makino, Yuichi; Johnson, Richard C; Yu, Yilin et al. (2011) Enhanced synaptic plasticity in mice with phosphomimetic mutation of the GluA1 AMPA receptor. Proc Natl Acad Sci U S A 108:8450-5
Smith-Hicks, Constance; Xiao, Bo; Deng, Rongkang et al. (2010) SRF binding to SRE 6.9 in the Arc promoter is essential for LTD in cultured Purkinje cells. Nat Neurosci 13:1082-9
Hayashi, Takashi; Thomas, Gareth M; Huganir, Richard L (2009) Dual palmitoylation of NR2 subunits regulates NMDA receptor trafficking. Neuron 64:213-26
Xie, Zhong; Photowala, Huzefa; Cahill, Michael E et al. (2008) Coordination of synaptic adhesion with dendritic spine remodeling by AF-6 and kalirin-7. J Neurosci 28:6079-91

Showing the most recent 10 out of 15 publications