Scientific Understanding of Consciousness
NMDA Receptor Ion Channel Crystal Structure
Science 30 May 2014: Vol. 344 no. 6187 pp. 992-997
Crystal structure of a heterotetrameric NMDA receptor ion channel
Erkan Karakas, Hiro Furukawa
Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
N-Methyl-d-aspartate (NMDA) receptors belong to the family of ionotropic glutamate receptors, which mediate most excitatory synaptic transmission in mammalian brains. Calcium permeation triggered by activation of NMDA receptors is the pivotal event for initiation of neuronal plasticity. Here, we show the crystal structure of the intact heterotetrameric GluN1-GluN2B NMDA receptor ion channel at 4 angstroms. The NMDA receptors are arranged as a dimer of GluN1-GluN2B heterodimers with the twofold symmetry axis running through the entire molecule composed of an amino terminal domain (ATD), a ligand-binding domain (LBD), and a transmembrane domain (TMD). The ATD and LBD are much more highly packed in the NMDA receptors than non-NMDA receptors, which may explain why ATD regulates ion channel activity in NMDA receptors but not in non-NMDA receptors.
Brain development and function rely on neuronal communication at a specialized junction called the synapse. In response to an action potential, neurotransmitters are released from the presynapse and activate ionotropic and metabotropic receptors at the postsynapse to generate a postsynaptic potential. Such synaptic transmission is a basis for experience-dependent changes in neuronal circuits. The majority of excitatory neurotransmission in the human brain is mediated by transmission of a simple amino acid, l-glutamate, which activates metabotropic and ionotropic glutamate receptors (mGluRs and iGluRs, respectively).
iGluRs are ligand-gated ion channels that comprise three major families, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) (GluA1-4), kainate (GluK1-5), and N-Methyl-d-aspartate (NMDA) receptors (GluN1, GluN2A-D, and GluN3A-B).
Non-NMDA receptors can form functional homotetramers that respond only to l-glutamate.
In contrast, NMDA receptors are obligatory heterotetramers mainly composed of two copies each of GluN1 and GluN2, which activate upon concurrent binding of glycine or d-serine to GluN1 and l-glutamate to GluN2 and relief of a magnesium block of the ion channel pore by membrane depolarization. Opening of NMDA receptor channels results in an influx of calcium ions that triggers signal transduction cascades that control the strength of neural connectivity or neuroplasticity. Hyper- or hypo-activation of NMDA receptors is implicated in neurological disorders and diseases including Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia, and ischemic injuries associated with stroke
The NMDA receptor subunits, like other iGluR subunits, contain modular domains that are responsible for controlling distinct functions.
In NMDA receptors:
An amino terminal domain (ATD) contributes to control of ion channel open probability and deactivation speeds and contains binding sites for subtype-specific allosteric modulator compounds, including zinc (GluN2A and 2B), ifenprodil (GluN2B), and polyamines (GluN2B).
A ligand-binding domain (LBD) binds agonists and antagonists to control ion channel opening.
A transmembrane domain (TMD) forms the heterotetrameric ion channel.
A carboxyl terminal domain (CTD) associates with postsynaptic density proteins, which in turn facilitates intracellular signaling pivotal for neuroplasticity.
In non-NMDA receptors:
The ATD does not regulate ion channel activity, the LBD binds only one agonist, l-glutamate, and the TMD forms an ion channel pore with no voltage-sensing capacity and with substantially less calcium permeability than NMDA receptors. The much shorter CTD interacts with postsynaptic proteins that are distinct from the NMDA receptor–associating proteins. Thus, despite being categorized in the same iGluR family, non-NMDA receptors and NMDA receptors have clear differences in basic ion channel physiology and pharmacology.
The only crystal structure of an intact iGluR is the homotetrameric GluA2 AMPA receptor bound to an antagonist. In NMDA receptor families, structural information has been limited to that of isolated ATD and LBD extracellular domains. Thus, the modes of subunit and domain arrangement of intact heterotetrameric NMDA receptors have remained enigmatic. Moreover, the structure-function relation of NMDA receptors has been difficult to dissect because functions such as ATD-mediated allosteric regulation, ligand-induced gating, and ion permeability occur in the context of heterotetramers and involve intersubunit and interdomain interactions. Thus, to facilitate understanding of complex functions in NMDA receptors, we sought to capture the pattern of intersubunit and interdomain arrangement by crystallographic studies on the intact heterotetrameric GluN1a-GluN2B NMDA receptor ion channel.
[end of paraphrase]
Return to — Neurons and Synapses