This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glutamate receptors are the primary excitatory receptors in the CNS of vertebrates. NMDA receptors, a class of glutamate receptors that are activated by N-methyl-D-aspartate, play an important role in learning and memory. NMDA receptor ion channels are permeable to Na+, K+, and Ca2+. The Ca2+ currents associated with NMDA receptors are believed to play an important role in synaptic plasticity, including induction of long-term potentiation and long-term depression. NMDA receptors feature strong voltage dependence due to Mg2+ block. 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, which is important for understanding Mg2+ block and ion selectivity. In order to study channel structure, We will build a theoretical structural model of the NMDA receptor channel and experimentally test its validity. 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. An initial homology model of the NMDA receptor channel based on the NaK channel was built by Beth Siegler Retchless, a graduate student in my lab, and successfully predicted a residue on NR1 and a residue on NR2A that interact with each other. Daniel Smith, also a graduate student in my lab, expanded Ms. Siegler Retchless's model to include more of the protein that forms the channel and will use theoretical chemistry techniques including homology modeling and MD simulations to develop a more accurate and complete model of the channel structure of NMDA receptors. The primary goal of this project is to develop a better understanding of the structure of the NMDA receptor channel and how its structure explains its unique physiological properties. We will study the subunit-subunit interactions that give the channel its shape, will use our model to predict interacting residues, and will experimentally test our predictions.
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