title: Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes.
abstract: Recent genome projects for ctenophores have revealed the presence of numerous ionotropic glutamate receptors (iGluRs) in Mnemiopsis leidyi and Pleurobrachia bachei, among our earliest metazoan ancestors. Sequence alignments and phylogenetic analysis show that these form a distinct clade from the well-characterized AMPA, kainate, and NMDA iGluR subtypes found in vertebrates. Although annotated as glutamate and kainate receptors, crystal structures of the ML032222a and PbiGluR3 ligand-binding domains (LBDs) reveal endogenous glycine in the binding pocket, whereas ligand-binding assays show that glycine binds with nanomolar affinity; biochemical assays and structural analysis establish that glutamate is occluded from the binding cavity. Further analysis reveals ctenophore-specific features, such as an interdomain Arg-Glu salt bridge, present only in subunits that bind glycine, but also a conserved disulfide in loop 1 of the LBD that is found in all vertebrate NMDA but not AMPA or kainate receptors. We hypothesize that ctenophore iGluRs are related to an early ancestor of NMDA receptors, suggesting a common evolutionary path for ctenophores and bilaterian species, and suggest that future work should consider both glycine and glutamate as candidate neurotransmitters in ctenophore species.
authors.affiliation: Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Robert
authors.initials: R
authors.lastname: Alberstein
authors.affiliation: Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Richard
authors.initials: R
authors.lastname: Grey
authors.affiliation: Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Austin
authors.initials: A
authors.lastname: Zimmet
authors.affiliation: The Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, FL 32080.
authors.forename: David K
authors.initials: DK
authors.lastname: Simmons
authors.affiliation: Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; mayerm@mail.nih.gov.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Mayer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D037302:Ctenophora / Q000145:classification / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D008969:Molecular Sequence Data; D010802:Phylogeny; D017470:Receptors, Glutamate / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D007473:Ion Channels; D017470:Receptors, Glutamate; D005998:Glycine
keywords: NMDA receptors; crystal structures; ctenophores; evolution