Ligand-gated ion channels (LGICs, also called ionotropic receptors) are transmembrane proteins that allow the flow of selected ions across the membrane in response to the binding of a chemical ligand (such as a neurotransmitter). In the central nervous system, LGICs mediate fast synaptic transmission on the millisecond time scale. This fast conversion from the chemical energy into the mechanical gating energy is essential for synaptic transmission. LGICs comprise both the excitatory (cation-selective) and the inhibitory (anion-selective) receptors. The dysfunction of the LGICs are involved in many psychiatric and neurological diseases including depression, schizophrenia, Parkinson's disease, and Alzheimer's disease.
More recently, the full-length structures of several key LGICs have been elucidated at atomic resolution, including the glutamate-gated tetrameric NMDA receptor (Lee et al, 2014) and AMPA receptor (Sobolevsky et al, 2009), ATP-gated trimeric P2X receptor (Kawate et al, 2009), glycine-gated pentameric GlyR receptor (Du et al, 2015). Structure exploration combined with ever more detailed functional studies is starting to reveal unanticipated diversity in allosteric modulation, pharmacology, gating mechanisms and conformational dynamics of various superfamilies of LGICs. By combining various approached in molecular and cellular biology, electrophysiology, pharmacology, and structural biology, our laboratory aims at deciphering the structure-function relationship of several key LGICs under both physiological and pathological conditions.
Molecular basis underlying autoimmune encephalitis
Autoimmune encephalitis is a recently-discovered autoimmune brain disease occurring when auto-antibodies produced by the body's own immune system attack neuronal receptors (including NMDA receptors, AMPA receptors and GABAB receptors) in the brain. Since these neuronal receptors play predominant roles in synaptic transmission and plasticity that are essential for the memory formation and retrieval, the targeting of auto-antibody to these receptors causes a variety of neuropathological symptoms. Our laboratory focuses on the identification the binding pocket of these auto-antibodies on the neuronal receptors, and elucidation the pathological mechanisms due to the interaction of auto-antibodies with these neuronal receptors.
Neuropharmacology based on structure and computational biology
Ionotropic glutamate receptors (iGluRs) are a major class of excitatory LGICs in the mammalian brain. They have triggered intense interest as potential drug targets because both hyper- and hypo-activation have been implicated in a wide range of neurological and psychiatric disorders. However, iGluRs-based therapy has yet to be turned into clinical success. Most of the competitive antagonists and channel blockers failed in clinical trials due to intolerable side effects and the lack of subunit specificity. We are interested in identifying small compounds that may act as positive and negative allosteric modulators of specific iGluR subtypes.