Nat Struct Mol Biol
December 2024
Antibodies against N-methyl-D-aspartate receptors (NMDARs) are most frequently detected in persons with autoimmune encephalitis (AE) and used as diagnostic biomarkers. Elucidating the structural basis of monoclonal antibody (mAb) binding to NMDARs would facilitate the development of targeted therapy for AE. Here, we reconstructed nanodiscs containing green fluorescent protein-fused NMDARs to label and sort individual immune B cells from persons with AE and further cloned and identified mAbs against NMDARs.
View Article and Find Full Text PDFBackground And Purpose: Sevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects.
Experimental Approach: To assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole-cell patch-clamp recordings, to examine the effects on GluN1-GluN2 incorporated N-methyl-d-aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC).
N-methyl-D-aspartate (NMDA) receptors are critical for brain function and serve as drug targets for the treatment of neurological and psychiatric disorders. They typically form the tetrameric assembly of GluN1-GluN2 (2A to 2D) subtypes, with their diverse three-dimensional conformations linked with the physiologically relevant function in vivo. Purified proteins of tetrameric assembled NMDA receptors have broad applications in the structural elucidation, hybridoma technology for antibody production, and high-throughput drug screening.
View Article and Find Full Text PDFWhole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.
View Article and Find Full Text PDFCurr Opin Neurobiol
December 2023
N-methyl-d-aspartate receptors (NMDARs) belong to the ionotropic glutamate receptors (iGluRs) superfamily and act as coincidence detectors that are crucial to neuronal development and synaptic plasticity. They typically assemble as heterotetramers of two obligatory GluN1 subunits and two alternative GluN2 (from 2A to 2D) and/or GluN3 (3A and 3B) subunits. These alternative subunits mainly determine the diverse biophysical and pharmacological properties of different NMDAR subtypes.
View Article and Find Full Text PDFN-methyl-D-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits. Here we report full-length cryo-EM structures of the human N1-N2D di-heterotetramer (di-receptor), rat N1-N2C di-receptor and N1-N2A-N2C tri-heterotetramer (tri-receptor) at a best resolution of 3.0 Å.
View Article and Find Full Text PDFKetamine, functioning as a channel blocker of the excitatory glutamate-gated N-methyl-d-aspartate (NMDA) receptors, displays compelling fast-acting and sustained antidepressant effects for treatment-resistant depression. Over the past decades, clinical and preclinical studies have implied that the pathology of depression is associated with dysfunction of glutamatergic transmission. In particular, the discovery of antidepressant agents modulating NMDA receptor function has prompted breakthroughs for depression treatment compared with conventional antidepressants targeting the monoaminergic system.
View Article and Find Full Text PDFN-methyl-D-aspartate receptors (NMDARs) are Ca-permeable ionotropic glutamate receptors (iGluRs) in the central nervous system and play important roles in neuronal development and synaptic plasticity. Conventional NMDARs, which typically comprise GluN1 and GluN2 subunits, have different biophysical properties than GluN3-containing NMDARs: GluN3-containing NMDARs have smaller unitary conductance, less Ca-permeability and lower Mg-sensitivity than those of conventional NMDARs. However, there are very few specific modulators for GluN3-containing NMDARs.
View Article and Find Full Text PDFKetamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant.
View Article and Find Full Text PDFN-methyl-D-aspartate (NMDA) receptors are glutamate-gated calcium-permeable ion channels that are widely implicated in synaptic transmission and plasticity. Here, we report a gallery of cryo-electron microscopy (cryo-EM) structures of the human GluN1-GluN2A NMDA receptor at an overall resolution of 4 Å in complex with distinct ligands or modulators. In the full-length context of GluN1-GluN2A receptors, we visualize the competitive antagonists bound to the ligand-binding domains (LBDs) of GluN1 and GluN2A subunits, respectively.
View Article and Find Full Text PDFEur J Hum Genet
September 2021
PANX1, one of the members of the pannexin family, is a highly glycosylated channel-forming protein. Recently, we identified heterozygous variants in PANX1 that follow an autosomal dominant inheritance pattern and cause female infertility characterized by oocyte death. In this study, we screened for novel PANX1 variants in patients with the phenotype of oocyte death and discovered a new type of inheritance pattern accompanying PANX1 variants.
View Article and Find Full Text PDFThe hypothalamus regulates innate social interactions, but how hypothalamic neurons transduce sex-related sensory signals emitted by conspecifics to trigger appropriate behaviors remains unclear. Here, we addressed this issue by identifying specific hypothalamic neurons required for sensing conspecific male cues relevant to inter-male aggression. By in vivo recording of neuronal activities in behaving mice, we showed that neurons expressing dopamine transporter (DAT) in the ventral premammillary nucleus (PMv) of the hypothalamus responded to male urine cues in a vomeronasal organ (VNO)-dependent manner in naive males.
View Article and Find Full Text PDFConnexins and pannexins are two protein families that play an important role in cellular communication. Pannexin 1 (PANX1), one of the members of pannexin family, is a channel protein. It is glycosylated and forms three species, GLY0, GLY1, and GLY2.
View Article and Find Full Text PDFHerein we provide a mass spectrometry-based lysine reactivity profiling strategy to monitor the ligand modulation of protein receptors, which is achieved by active dimethyl labeling of lysine residues and comparison of the alterations of labeling reactivity during ligand binding. The small-molecule ligand modulation patterns on the catechol-O-methyltransferase and the N-methyl-d-aspartate receptors have been predicted, including both binding regions and related conformational changes.
View Article and Find Full Text PDFN-methyl-D-aspartate (NMDA) receptors are critical for synaptic development and plasticity. While glutamate is the primary agonist, protons can modulate NMDA receptor activity at synapses during vesicle exocytosis by mechanisms that are unknown. We used cryo-electron microscopy to solve the structures of the human GluN1-GluN2A NMDA receptor at pH 7.
View Article and Find Full Text PDFNeuropharmacology
January 2017
Ionotropic glutamate receptors (iGluRs) transduce signals derived from release of the excitatory neurotransmitter glutamate from pre-synaptic neurons into excitation of post-synaptic neurons on a millisecond time-scale. In recent years, the elucidation of full-length iGluR structures of NMDA, AMPA and kainate receptors by X-ray crystallography and single particle cryo-electron microscopy has greatly enhanced our understanding of the interrelationships between receptor architecture and gating mechanism. Here we briefly review full-length iGluR structures and discuss the similarities and differences between NMDA receptors and non-NMDA iGluRs.
View Article and Find Full Text PDFN-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states and how small molecules inhibit or activate ion channel gating.
View Article and Find Full Text PDFLigand-gated ion channels (LGICs) mediate fast synaptic transmission in the CNS. Typically, these membrane proteins are multimeric complexes associating several homologous subunits around a central pore. Because of the large repertoire of subunits within each family, LGICs exist in vivo as multiple subtypes that differ in subunit composition and functional properties.
View Article and Find Full Text PDFCurr Opin Pharmacol
February 2015
N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are essential mediators of excitatory neurotransmission and synaptic plasticity. NMDARs are also implicated in a plethora of neuropathological conditions thus receiving strong interest as potential therapeutic targets. Recent years have witnessed major progress in our understanding of the structure and pharmacology of NMDARs with the decoding of the first full-length receptor crystal structures and the discovery of allosteric modulators acting at novel binding sites and with unique patterns of subunit selectivity.
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