The overall goal of my efforts is to define molecular features of synaptic transmission in the nervous system by studying the operation of NMDA and AMPA receptors. These receptors are neurotransmitter-gated ion channels that convert the presynaptic release of glutamate, the predominant excitatory neurotransmitter in the brain, into a postsynaptic signal. By defining the operation of NMDA and AMPA receptors, we will gain a better understanding of how they control brain function. We will also learn how to modulate their function with greater precision and specificity to help understand, and potentially treat, disease states such as schizophrenia, epilepsy, and the excitotoxicity associated with acute and chronic brain disorders. Our experiments will focus on structural elements of the NMDA and AMPA receptor located to the periphery of those lining the permeation pathway of the ion channel. Recent evidence has indicated that inherited and de novo mutations in these outer or peripheral structures induce developmental disorders and epileptic encephalopathies. These outer structures also contain allosteric sites for drugs of abuse and are targets for newly developed NMDA receptor modulators.
Aim 1 will address the impact of the outer structures to the rapid and efficient pore opening that is the hallmark of fast synaptic transmission. For these experiments, we will combine single channel recordings with non-equilibrium conditions to define the energetics of displacement of the outer structures.
Aim 2 will address how permeant ions access the central permeation pathway through the outer structures.
Aim 3 will address how disease- causing mutations interact at the outer structures to alter NMDA and AMPA receptor function. Here, we will use cysteine cross-linking, fast agonist application, and agonist-free single channel recordings to address how specific elements interact in the outer structures to modulate receptor function. Overall our experiments will delineate how the outer structures contribute to the operation of NMDA and AMPA receptors. This information will aid in defining how disease-causing mutations affect receptor function and in developing specific therapies to target these receptors in nervous system disorders.

Public Health Relevance

Schizophrenia, epilepsy, and the excitotoxicity associated with acute and chronic brain diseases have a devastating impact on human lives and society. This project addresses the operation of NMDA and AMPA receptors, neurotransmitter-gated ion channels that mediate brain function and are involved in numerous brain disorders. The outcome of our experiments will aid in the development of translational therapies to target these receptors in specific nervous system disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS088479-04
Application #
9440460
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Silberberg, Shai D
Project Start
2015-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Amin, Johansen B; Salussolia, Catherine L; Chan, Kelvin et al. (2017) Divergent roles of a peripheral transmembrane segment in AMPA and NMDA receptors. J Gen Physiol 149:661-680
Zhou, Huan-Xiang; Wollmuth, Lonnie P (2017) Advancing NMDA Receptor Physiology by Integrating Multiple Approaches. Trends Neurosci 40:129-137
Gan, Quan; Dai, Jian; Zhou, Huan-Xiang et al. (2016) The Transmembrane Domain Mediates Tetramerization of ?-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors. J Biol Chem 291:6595-606
Alsaloum, Matthew; Kazi, Rashek; Gan, Quan et al. (2016) A Molecular Determinant of Subtype-Specific Desensitization in Ionotropic Glutamate Receptors. J Neurosci 36:2617-22
Dai, Jian; Wollmuth, Lonnie P; Zhou, Huan-Xiang (2015) Mechanism-Based Mathematical Model for Gating of Ionotropic Glutamate Receptors. J Phys Chem B 119:10934-40