Chemical synapses are connections between neurons in the human central nervous system that are fundamental to its development and normal function. At these points of nerve cell - nerve cell interaction, a chemical transmitter released from one cell diffuses across a small space, called the synapse, to receptors located on the opposing cell, triggering the opening of ligand-gated ion channels and the activation of other cell surface receptors. At excitatory synapses, the opening or activation of ligand-gated ion channels causes the influx of primarily sodium and calcium ions, depolarizing the cell and injecting a potent calcium signal. The activation and modulation of ligand- gated ion channels is thus a crucial component of signal transmission in the central nervous system. In this grant application, I propose to study the atomic structure of ionotropic glutamate receptors and acid sensing ion channels, two ubiquitous and important classes of ligand-gated ion channel. In the proposed experiments on essential fragments of the receptors, as well as on the intact receptors, I will define the precise atomic structure of these ligand-gated ion channels and will determine mechanisms of ion channel activation, inhibition and modulation. The proposed studies will reveal basic principles of ligand-gated ion channel function and they will also provide crucial molecular blueprints to guide the development of new pharmacological agents to treat debilitating diseases of the human nervous system.
Glutamate receptors and acid sensing ion channels are ligand-gated ion channel proteins that are essential to the normal development and function of the human nervous system and are integral to such fundamental processes as learning and memory. In this proposal we aim to determine their molecular structures and define principles for their activity, and thereby provide a foundation for development of new therapeutic agents to treat diseases of the human nervous system.
|Chen, Shanshuang; Zhao, Yan; Wang, Yuhang et al. (2017) Activation and Desensitization Mechanism of AMPA Receptor-TARP Complex by Cryo-EM. Cell 170:1234-1246.e14|
|Zhu, Shujia; Stein, Richard A; Yoshioka, Craig et al. (2016) Mechanism of NMDA Receptor Inhibition and Activation. Cell 165:704-14|
|Zhao, Yan; Chen, Shanshuang; Yoshioka, Craig et al. (2016) Architecture of fully occupied GluA2 AMPA receptor-TARP complex elucidated by cryo-EM. Nature 536:108-11|
|Lee, Chia-Hsueh; Lü, Wei; Michel, Jennifer Carlisle et al. (2014) NMDA receptor structures reveal subunit arrangement and pore architecture. Nature 511:191-7|
|Chen, Lei; Dürr, Katharina L; Gouaux, Eric (2014) X-ray structures of AMPA receptor-cone snail toxin complexes illuminate activation mechanism. Science 345:1021-6|
|Goehring, April; Lee, Chia-Hsueh; Wang, Kevin H et al. (2014) Screening and large-scale expression of membrane proteins in mammalian cells for structural studies. Nat Protoc 9:2574-85|
|Baconguis, Isabelle; Bohlen, Christopher J; Goehring, April et al. (2014) X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel. Cell 156:717-29|
|Dürr, Katharina L; Chen, Lei; Stein, Richard A et al. (2014) Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states. Cell 158:778-792|
|Baconguis, Isabelle; Hattori, Motoyuki; Gouaux, Eric (2013) Unanticipated parallels in architecture and mechanism between ATP-gated P2X receptors and acid sensing ion channels. Curr Opin Struct Biol 23:277-84|
|Baconguis, Isabelle; Gouaux, Eric (2012) Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes. Nature 489:400-5|