This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Glutamate receptors are the primary excitatory receptors in the central nervous sytem (CNS) of vertebrates. NMDA receptors, a class of glutamate receptors that are activated by N-methyl-D-aspartate, play an important role in learning, memory, and many CNS disorders. NMDA receptor ion channels are permeable to Na+, K+, and Ca2+. The Ca2+ currents associated with NMDA receptors are believed essential in synaptic plasticity, including induction of long-term potentiation and long-term depression. NMDA receptors feature strong voltage dependence due to Mg2+ block, a regulatory mechanism of profound physiological significance. At resting potentials, NMDA currents are highly blocked, but membrane depolarization alleviates Mg2+ block. There has been much research into the structure and function of NMDA receptors, but key components of the physical structure of NMDA receptors remain unknown. While there have been studies documenting the accessibility of particular residues along the pore and on other portions of the receptor's transmembrane regions, there is little atomic level information on overall channel structure and function, which is important for understanding Mg2+ block and ion selectivity. In order to study channel structure, I have built a structural homology model of the NMDA receptor channel and intend to test its validity using structure scoring programs. The NaK channel, which, like NMDA receptors, conducts Na+ and K+, has a moderate amount of sequence homology and is believed to have similar structure to the NMDA receptor channel. Likewise, the pore lining sections of KCSA channel and NMDA receptors are believed to be homologous. A set of homology models of the NMDA receptor channel based on the NaK channel have built by Beth Siegler Retchless, a graduate student in my lab, which successfully predicted a residue on NR1 and a residue on NR2A that interact with each other. The models have been refined by Daniel Smith, also a graduate student in my lab. The primary goal of this project is to develop a better understanding the physical basis of the selectivity of NMDA receptor channels that results in high permeability to Ca2+ but potent block by Mg2+. The techniques we are using to study Ca2+ selectivity are being tested on molecular dynamics models of the chemicals EGTA (ethylene glycol tetraacetic acid) and EDTA (ethylenediaminetetraacetic acid). The structures of EGTA and EDTA are very similar. However, EGTA is selective for Ca2+ over Mg2+ while EDTA is not.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
3P41RR006009-20S1
Application #
8364297
Study Section
Special Emphasis Panel (ZRG1-BCMB-Q (40))
Project Start
2011-09-15
Project End
2013-07-31
Budget Start
2011-09-15
Budget End
2013-07-31
Support Year
20
Fiscal Year
2011
Total Cost
$1,094
Indirect Cost
Name
Carnegie-Mellon University
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Yonkunas, Michael; Buddhadev, Maiti; Flores Canales, Jose C et al. (2017) Configurational Preference of the Glutamate Receptor Ligand Binding Domain Dimers. Biophys J 112:2291-2300
Earley, Lauriel F; Powers, John M; Adachi, Kei et al. (2017) Adeno-associated Virus (AAV) Assembly-Activating Protein Is Not an Essential Requirement for Capsid Assembly of AAV Serotypes 4, 5, and 11. J Virol 91:
Subramanian, Sandeep; Chaparala, Srilakshmi; Avali, Viji et al. (2016) A pilot study on the prevalence of DNA palindromes in breast cancer genomes. BMC Med Genomics 9:73
Ramakrishnan, N; Tourdot, Richard W; Radhakrishnan, Ravi (2016) Thermodynamic free energy methods to investigate shape transitions in bilayer membranes. Int J Adv Eng Sci Appl Math 8:88-100
Zhang, Yimeng; Li, Xiong; Samonds, Jason M et al. (2016) Relating functional connectivity in V1 neural circuits and 3D natural scenes using Boltzmann machines. Vision Res 120:121-31
Lee, Wei-Chung Allen; Bonin, Vincent; Reed, Michael et al. (2016) Anatomy and function of an excitatory network in the visual cortex. Nature 532:370-4
Murty, Vishnu P; Calabro, Finnegan; Luna, Beatriz (2016) The role of experience in adolescent cognitive development: Integration of executive, memory, and mesolimbic systems. Neurosci Biobehav Rev 70:46-58
Lee, Tai Sing (2015) The visual system's internal model of the world. Proc IEEE Inst Electr Electron Eng 103:1359-1378
Kuhlman, Chris J; Anil Kumar, V S; Marathe, Madhav V et al. (2015) Inhibiting diffusion of complex contagions in social networks: theoretical and experimental results. Data Min Knowl Discov 29:423-465
Jurkowitz, Marianne S; Patel, Aalapi; Wu, Lai-Chu et al. (2015) The YhhN protein of Legionella pneumophila is a Lysoplasmalogenase. Biochim Biophys Acta 1848:742-51

Showing the most recent 10 out of 289 publications