Activity of Minimal NMDA Receptors

点击翻译按钮获取中文摘要

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.