Scientific Understanding of Consciousness
NMDAR Receptor Structure
Nature 511, 162–163 (10 July 2014)
Neuroscience: A structure to remember
David Stroebel & Pierre Paoletti
Institute of Biology, École Normale Supérieure, CNRS UMR8197, INSERM U1024, 75005 Paris, France.
Since their discovery more than 30 years ago, N-methyl-D-aspartate receptors (NMDARs) have fascinated neuroscientists. They are key mediators of synaptic plasticity, the cellular mechanism mediating information storage in the brain. Moreover, dysfunctions of NMDARs are implicated in various neuropsychiatric disorders, from schizophrenia to mental retardation and epilepsy, making them targets of therapeutic interest. Two research studies present the long-awaited molecular structure of an NMDAR subtype, the GluN1–GluN2B receptor, from rats and frogs, respectively. These atomic maps offer unprecedented views and a wealth of information about a key brain receptor.
Together with the AMPA receptors (AMPARs) and kainate receptors, the NMDARs belong to the superfamily of ionotropic glutamate receptors (iGluRs), which mediate excitatory communication between neurons in the central nervous system. The iGluRs are massive protein complexes embedded in the neuronal cell membrane. Each complex contains more than 3,400 amino-acid residues, and is composed of four subunits. Each subunit has a typical modular architecture made up of a large extracellular amino-terminal domain (ATD) that participates in subtype-specific receptor assembly and modulation; a ligand-binding domain (LBD) that binds receptor-activating agonist molecules; a transmembrane domain (TMD) that forms an ion-channel pore; and a cytoplasmic carboxy-terminal domain (CTD) involved in receptor trafficking and coupling to intracellular signalling molecules.
However, NMDARs differ from other iGluRs in several respects. First, their transmembrane pore is highly permeable to calcium ions and is blocked by magnesium ions — features that are essential for triggering synaptic plasticity. Second, their LBDs require two different agonists for activation. And finally, their ATDs form a major regulatory region that harbours several binding sites for subunit-specific modulators.
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Nature 511, 191–197 (10 July 2014)
NMDA receptor structures reveal subunit arrangement and pore architecture
Chia-Hsueh Lee, et.al.
Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
Howard Hughes Medical Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
N-methyl-d-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the development and function of the brain, a molecular structure of an intact receptor has remained elusive. Here we present X-ray crystal structures of the Xenopus laevis GluN1–GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino-terminal and ligand-binding domains. The transmembrane domains harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a ~twofold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.
Glutamate is the primary excitatory neurotransmitter in the brain, acting at ionotropic and metabotropic glutamate receptors. Rapid excitation by glutamate, in turn, solely involves action at AMPA, kainate and NMDA ionotropic glutamate receptors. The NMDA receptor is central to the development and function of the nervous system and to neurotoxicity. As a linchpin of synaptic plasticity, blockade of the NMDA receptor interferes with memory formation and recall. Moreover, mutations within the coding regions of NMDA receptor subunit genes are associated with a spectrum of neurological diseases and neuropsychiatric disorders, from schizophrenia to epilepsy. Autoimmune responses to the NMDA receptor, and presumed disruption in NMDA receptor organization on neural cell surfaces, probably underlie NMDA receptor encephalitis. In keeping with the profound roles of the NMDA receptor in brain function, the receptor is a target of small molecules for the treatment of cognitive impairment, depression, schizophrenia and pain.
Although AMPA and kainate receptors can be activated solely by glutamate, NMDA receptors are Hebbian-like coincidence detectors, requiring the binding of glycine and glutamate to GluN1 and GluN2 subunits, respectively, combined with membrane depolarization to relieve magnesium block. Activation of the receptor opens a cation-selective, calcium-permeable channel, thus causing further depolarization of the cell membrane and influx of calcium.
NMDA receptors are obligatory heterotetrameric assemblies, usually composed of two glycine-binding GluN1 subunits and two glutamate-binding GluN2A-D subunits, with the GluN1–GluN2A–GluN2B complex as the predominant NMDA receptor at hippocampal synapses. Glycine- and d-serine-binding GluN3 subunits are additional subunits, expressed throughout the nervous system, but with roles less well defined in comparison to the GluN1–GluN2 assemblies. A hallmark of NMDA receptors, by contrast with AMPA and kainate receptors, is a wide spectrum of allosteric modulation, from nanomolar concentrations of zinc, to the small molecule ifenprodil, polyamines and protons and to voltage-dependent ion channel block by MK-801, ketamine and memantine.
The GluN1, GluN2 and GluN3 NMDA receptor subunits are related in amino acid sequence and, like AMPA and kainate receptor subunits, possess a modular domain architecture, with amino-terminal domains (ATDs) and ligand-binding domains (LBDs) on the extracellular side of the membrane, a transmembrane domain (TMD) spanning the membrane and defining the ion channel pore, and an intracellular carboxy-terminal domain (CTD) within the cytoplasm. Multiple high-resolution crystal structures of the isolated LBDs from NMDA, AMPA and kainate receptors show that these domains adopt similar clamshell-like structures that are organized in an approximately dimeric, back-to-back fashion.
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