NMDA receptors have received a great deal of attention because of their role in synaptic plasticity, seizure initiation, and ischemia-induced neuronal death. Recent crystallographic advances have provided the first structure for the agonist binding domains of NR1 and NR2A subunits, and recent functional studies have provided the first conceptual models of NR1/NR2A receptor activation that account for both single channel and macroscopic properties. These advances create an ideal opportunity to explore in detail the relationship between structure and function for NMDA receptors. We will evaluate function in the context of structure for NR1/NR2C and NR1/NR2D receptors, which remain poorly understood despite their roles in striatal and cerebellar function and the intriguing therapeutic potential of NR2C/NR2D subunit-selective modulators. The proposed experiments exploit our recent success in obtaining outside-out membrane patches that contain only one active channel to examine the function of NR1/NR2C and NR1/NR2D receptors activated by both glutamate and novel subunit-selective agonists and modulators. Single channel studies will be extended to native NR2D-containing receptors and recombinant heterotrimeric receptors containing two different NR2 subunits, which can be unambiguously isolated in one channel patches. Complementary experiments will exploit structural data by using atomic co-variance analysis of molecular dynamics simulations of the agonist binding domains for all NR1/NR2 combinations to evaluate long-range intra-protein motions. Our preliminary data reveal intra-protein motions that show domain closure, a pivot around the NR1/NR2 dimer interface, and different interdomain contacts between functionally dissimilar NR2A and NR2D. Understanding the relationship between structure and function is a pre-requisite to rational drug design, which may ultimately yield therapeutically relevant compounds. Proposed experiments will address four questions. 1. How do the NR2C and NR2D subunits control NMDA receptor activation? 2. What are the functional properties of heterotrimeric NR1/NR2A/NR2D and NR1/NR2B/NR2D receptors? 3. How does the NR2D subunit control native NMDA receptor activation? 4. What structural features of the NR1/NR2 dimer influence intra-protein motion and receptor activation?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37NS036654-14
Application #
8290600
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Silberberg, Shai D
Project Start
1998-07-10
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
14
Fiscal Year
2011
Total Cost
$370,783
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Bhattacharya, Subhrajit; Khatri, Alpa; Swanger, Sharon A et al. (2018) Triheteromeric GluN1/GluN2A/GluN2C NMDARs with Unique Single-Channel Properties Are the Dominant Receptor Population in Cerebellar Granule Cells. Neuron 99:315-328.e5
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Perszyk, Riley; Katzman, Brooke M; Kusumoto, Hirofumi et al. (2018) An NMDAR positive and negative allosteric modulator series share a binding site and are interconverted by methyl groups. Elife 7:
Bhattacharya, Subhrajit; Traynelis, Stephen F (2018) Unique Biology and Single-Channel Properties of GluN2A- and GluN2C-Containing Triheteromeric N-Methyl-D-Aspartate Receptors. J Exp Neurosci 12:1179069518810423
Singh, Arun; Jenkins, Meagan A; Burke Jr, Kenneth J et al. (2018) Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates. Cell Rep 22:941-952
Liu, Shuxi; Zhou, Liang; Yuan, Hongjie et al. (2017) A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density. J Neurosci 37:4093-4102
Strong, Katie L; Epplin, Matthew P; Bacsa, John et al. (2017) The Structure-Activity Relationship of a Tetrahydroisoquinoline Class of N-Methyl-d-Aspartate Receptor Modulators that Potentiates GluN2B-Containing N-Methyl-d-Aspartate Receptors. J Med Chem 60:5556-5585
Platzer, Konrad; Yuan, Hongjie; Schütz, Hannah et al. (2017) GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet 54:460-470

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