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. This proposal involves three different and unique integral membrane proteins: (1) a eukaryotic pentameric 'Cys-loop'receptor;(2) a eukaryotic P2X ion channel;and (3) a eukaryotic, full-length ionotropic glutamate receptor (iGluR). We are studying the structure and function of so-called Cys-loop receptors of which the nicotinic acetylcholine receptor is perhaps the most well known example. These pentameric, ligand-gated ion channels play essential and widespread roles in human physiology, particularly in the nervous system, and are the targets of a broad spectrum of therapeutic agents and mood altering substances. We have crystals of a eukaryotic Cys-loop receptor that diffract to 3.2 ? resolution. The second project is focused on full-length P2X receptors. P2X receptors are ATP-gated ion channels that are present only in multicellular eukaryotes and that play key roles in nervous system. Last year we reported the structure of the zebra fish P2X4 receptor in an apo, closed state. Now we aim to solve structures in other functional states: open;closed-desensitized;closed-antagonist bound. These structures will not only shed light on the mechanism of P2X receptors but they may also facilitate the development of novel therapeutic agents. The third project involves studies of crystals of glutamate-gated ion channels, the linchpins of fast synaptic transmission in the human nervous system. Last year we also reported the first structure of the rat GluA2 AMPA-sensitive receptor in an antagonist-bound, closed state. Now we aim to solve the structures of the receptor in multiple functional states, including the agonist-bound, desensitized state and the agonist-bound open state.
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