MG2+ BLOCK AND CA2+ SELECTIVITY IN THE NMDA RECEPTOR

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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.