This project will characterize the functional properties of NMDA receptors that lack N-terminal and C-terminal
domains, herein referred to as minimal receptors. These proteins consist of the core machinery of NMDA
receptors and include the extracellular agonist-binding domain (ABD) connected to the ion-permeable pore
formed by the transmembrane (TMD) domain. In the parent project, we were successful in using a structural
model of this minimal receptor to envision the opening trajectory of NMDA receptors, using molecular dynamics
simulations. However, it is unknown whether the minimal receptors are functional and therefore whether they
represent a suitable model for further structure-function investigations, based on the hypotheses generated by
our simulations. In this application, we propose to investigate the hypothesis that minimal NMDA receptors
display glutamate-mediated ionotropy. Our preliminary results demonstrate that minimal receptors respond to
glutamate by producing excitatory currents that differ in kinetics from wild-type receptors. By delineating
commonalities and differences between the activation mechanism of minimal NMDA receptors and native
receptors, results from this project will provide information necessary for the correct interpretation of results
from molecular dynamics simulations.