NMDA receptors play critical roles in the regulation of synaptic plasticity, neuronal development and several neurological and psychiatric diseases. Recent studies have shown that NMDA receptors bind to the PSD95/SAP9O adaptor protein to form a large macromolecular signaling complex. The PSD95/SAP9O protein family appears to play a critical role in the synaptic targeting of NMDA receptors and in the coupling of NMDA receptors to downstream signal transduction pathways. 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. Recent studies in our lab have shown that phosphorylation of the NMDA receptor by a novel protein kinase disrupts receptor binding to the PSD95/SAP9O protein and thus may play a critical role in the regulation of NMDA receptor signaling. In the proposed research we plan to characterize the kinase responsible for this phosphorylation and examine the effect of this phosphorylation on NMDA receptor synaptic targeting and downstream signaling. Our laboratory has also recently shown that PSD95/SAP9O binds to a novel synapse specific rasGAP, SynGAP, which may regulate ras signaling at excitatory synapses. In this proposal we plan to analyze the role of SynGAP in the regulation of synaptic ras signaling and synaptic transmission and plasticity. The function of SynGAP will be studied in neurons transfected with wild-type and mutant forms of SynGAP and in recently obtained SynGAP knock-out mice. Finally, our laboratory has also recently found that the Rsk2 protein kinase binds to the synaptic scaffolding protein SHANK. SHANK is a component of the NMDA receptor complex that also interacts with several other synaptic proteins including GKAP, Homer and metabotropic glutamate receptors. Interestingly Rsk2 phosphorylates SHANK and may regulate the functional properties of the NMDA receptor complex. In this proposal we will further characterize the phosphorylation of SHANK by Rsk and analyze the functional effects of this phosphorylation on the regulation of synaptic function and plasticity. These studies investigate three different levels of the NMDA receptor protein complex and will help elucidate the function of this large macromolecular complex in excitatory synaptic function and its potential role in neurological and psychiatric diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH064856-01
Application #
6435735
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Asanuma, Chiiko
Project Start
2001-12-13
Project End
2006-11-30
Budget Start
2001-12-13
Budget End
2002-11-30
Support Year
1
Fiscal Year
2002
Total Cost
$408,750
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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

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