NMDA receptors (NMDARs) mediate a slow, Ca2+ permeable component of excitatory synaptic transmission, and play a central role in normal processes that are essential for life. In addition, a large number of neurological conditions either involve aberrant NMDAR function or the modulation of NMDAR function could be therapeutically beneficial. For these reasons, there is resurgent interest in the pharmacology of the NMDAR, with the discovery of multiple classes of subunit-selective modulators that act at 6 different modulatory sites on the receptor. This is in contrast to the preceding decade, during which NMDAR drug development was curtailed after multiple NMDAR antagonist trials for stroke failed, in part, due to factors unrelated to efficacy. These new modulator classes show a wide range of GluN2-subunit selectivity and diverse mechanisms, which include modulation of channel open probability, agonist potency, and deactivation time course, as well as a dependence on agonist binding. We have discovered two series of allosteric modulators that alter single channel conductance and ionic selectivity and block, establishing a new precedent in ion channel modulation. Analogous to regulation of biased signaling in GPCRs, our recent data suggest that we can regulate different facets of NMDAR function (current flow, Ca2+ permeation, Mg2+ block) through these new classes of modulators. Both classes of modulators have structural determinants located in the GluN1 pre-M1 helix, a gating motif that makes contact with the transmembrane M3 helix, which forms the channel gate. Moreover, there is a unique structure- activity relationship for the effect of modulators on ion permeation, as substitution at different positions on a phenyl ring can tune the relative proportion of subconductance levels. A deeper understanding of these properties might allow the development, for example, of NMDAR potentiators that do not trigger Ca2+- mediated neurotoxicity or biased modulators that do not alter response time course but reduce Ca2+ permeability. Such allosteric modulators should be free from on-target side effects yet may be neuroprotective for vulnerable regions, such as dopaminergic neurons in Parkinson?s patients. Given the potential utility of these novel modulators, we have designed 4 experiments that use medicinal chemistry, molecular biology, electrophysiology, and Ca2+ imaging to explore the site and mechanism of regulation of channel conductance and ionic selectivity.
Aim 1 : Do other classes of modulator acting on pre-M1 region alter single channel conductance? Aim 2: What is the structure-activity relationship for control of conductance and ionic selectivity? Aim 3: What are the key residues that control the different effects of these modulators? Aim 4: Do modulator-induced changes in conductance and Ca2+ permeability alter synaptic signaling?

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This proposal will evaluate the unique structure-activity relationship between novel positive and negative allosteric modulators that act at the NMDA receptor in a manner that is controlled by the GluN1 pre-M1 helix. These modulators reduce single channel conductance, decrease relative to Ca2+ permeability, enhance agonist potency, and prolong the deactivation time course. The goal is to understand this mechanism of action as well as what structural features of the molecules control the various properties of the modulators.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Silberberg, Shai D
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Emory University
Schools of Medicine
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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
Fry, Andrew E; Fawcett, Katherine A; Zelnik, Nathanel et al. (2018) De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain :
Hansen, Kasper B; Yi, Feng; Perszyk, Riley E et al. (2018) Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol 150:1081-1105
Bhattacharya, Subhrajit; Ma, Yuxian; Dunn, Amy R et al. (2018) NMDA receptor blockade ameliorates abnormalities of spike firing of subthalamic nucleus neurons in a parkinsonian nonhuman primate. J Neurosci Res 96:1324-1335
Swanger, Sharon A; Vance, Katie M; Acker, Timothy M et al. (2018) A Novel Negative Allosteric Modulator Selective for GluN2C/2D-Containing NMDA Receptors Inhibits Synaptic Transmission in Hippocampal Interneurons. ACS Chem Neurosci 9:306-319
Fernández-Marmiesse, Ana; Kusumoto, Hirofumi; Rekarte, Saray et al. (2018) A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder. Mov Disord 33:992-999
Kaiser, Thomas M; Kell, Steven A; Kusumoto, Hirofumi et al. (2018) The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor. Mol Pharmacol 93:141-156
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
Wells, Gordon; Yuan, Hongjie; McDaniel, Miranda J et al. (2018) The GluN2B-Glu413Gly NMDA receptor variant arising from a de novo GRIN2B mutation promotes ligand-unbinding and domain opening. Proteins 86:1265-1276

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