N-methyl-D-aspartate (NMDA) receptors are glutamate gated ion channels that play an important role in synaptic transmission, synaptic plasticity, and synapse formation. Inadequate or excessive NMDA receptor activity contributes to the pathogenesis of a wide variety of disorders including fetal alcohol syndrome, ethanol tolerance, alcoholism, schizophrenia, major depression, and posttraumatic stress disorder. For example, animals with reduced NMDA receptor surface expression exhibit schizophrenic-like behavior such as increased motor activity and deficits in social and sexual interactions. Efficient assembly and trafficking of NMDA receptors from the endoplasmic reticulum (ER) to the plasma membrane is a key step in regulating NMDA receptor activity. However, the cellular and molecular mechanisms regulating the release of NMDA receptors from the ER are entirely unknown. The objective of this proposal is to determine the key regulatory steps underlying NMDA receptor ER release and surface expression. To this end, I will identify intracellular domains that prevent ER release of NMDA receptors using a combination of immunocytochemical, biochemical, pharmacological and cell culture techniques. Second, I will determine the role intracellular second messengers or other NMDA receptor subunits play in regulating ER release of native channels. Understanding how NMDA receptors exit the ER and traffic to the plasma membrane may ultimately facilitate the design of alternative therapies useful in the treatment of alcoholism, fetal alcohol syndrome, and many psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AA013220-01
Application #
6339796
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Noronha, Antonio
Project Start
2001-09-01
Project End
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$23,599
Indirect Cost
Name
Duke University
Department
Biology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Schwantes-An, Tae-Hwi; Zhang, Juan; Chen, Li-Shiun et al. (2016) Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts. Behav Genet 46:151-69
Scott, Derek B; Michailidis, Ioannis; Mu, Yuanyue et al. (2004) Endocytosis and degradative sorting of NMDA receptors by conserved membrane-proximal signals. J Neurosci 24:7096-109
Scott, Derek B; Blanpied, Thomas A; Ehlers, Michael D (2003) Coordinated PKA and PKC phosphorylation suppresses RXR-mediated ER retention and regulates the surface delivery of NMDA receptors. Neuropharmacology 45:755-67
Blanpied, Thomas A; Scott, Derek B; Ehlers, Michael D (2003) Age-related regulation of dendritic endocytosis associated with altered clathrin dynamics. Neurobiol Aging 24:1095-104
Mu, Yuanyue; Otsuka, Takeshi; Horton, April C et al. (2003) Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors. Neuron 40:581-94
Blanpied, Thomas A; Scott, Derek B; Ehlers, Michael D (2002) Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron 36:435-49