title: Ion channels gated by acetylcholine and serotonin: structures, biology, and drug discovery.
abstract: The nicotinic acetylcholine receptors (nAChRs) and the 5-HT3 receptors (5-HT3Rs) are cation-selective members of the pentameric ligand-gated ion channels (pLGICs), which are oligomeric protein assemblies that convert a chemical signal into an ion flux through postsynaptic membrane. They are critical components for synaptic transmission in the nervous system, and their dysfunction contributes to many neurological disorders. The diverse subunit compositions of pLGICs give rise to complex mechanisms of ligand recognition, channel gating, and ion-selective permeability, which have been demonstrated in numerous electrophysiological and molecular biological studies, and unraveled by progress in studying the structural biology of this protein family. In this review, we discuss recent insights into the structural and functional basis of two cation-selective pLGICs, the nAChR and the 5-HT3R, including their subunit compositions, ligand binding, and channel gating mechanisms. We also discuss their relevant pharmacology and drug discovery for treating various neurological disorders. Finally, we review a model of two alternative ion conducting pathways based on the latest 5-HT3A crystal structure.
authors.affiliation: 1] Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China [2] VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zhong-shan
authors.initials: ZS
authors.lastname: Wu
authors.affiliation: VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.affiliation: VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.affiliation: 1] VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000495:Allosteric Site / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D012701:Serotonin / Q000378:metabolism*
chemical_list: D011950:Receptors, Cholinergic; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D000109:Acetylcholine