The glutamate receptor ion channels (original) (raw)

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Pharmacological Reviews, 2010

The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.

Regulation of Ionotropic Glutamate Receptors by Their Auxiliary Subunits

Physiology, 2010

Glutamate receptors are major excitatory receptors in the brain. Recent findings have established auxiliary subunits of glutamate receptors as critical modulators of synaptic transmission, synaptic plasticity and neurological disorder. The elucidation of the molecular rules governing glutamate receptors and subunits will improve our understanding of synapses and of neural-circuit regulation in the brain.

The unique properties of glutamate receptor channels

FEBS Letters, 1993

Rapid excitatory neurotransmission in the central nervous system (CNS) is mediated predominantly by synaptically released L-glutamate which activates cation selective channels with different kinetic and ion conductance properties. Studies with cloned glutamate receptor channels helped delineate the functional properties of channels defined in subunit composition. Moreover, molecular studies have revealed novel genetic mechanisms controlling the expression of important structural channel determinants. Channel determinant; Ca" permeability; RNA editing 90

Multi-level control of ionotropic glutamate receptor function

Cellscience, 2009

Because ionotropic glutamate receptors play critical roles in numerous CNS functions, there has been considerable interest in understanding molecular mechanisms regulating their properties. In particular, the search for ligands and corresponding binding sites providing allosteric regulation of agonist binding and channel opening and closing has been intensely pursued in the hope of developing new approaches for the treatment of a variety of CNS diseases associated with abnormal functioning of glutamatergic systems. Several recent publications have reported detailed structures of the N-terminal domains of NMDA and AMPA receptors and have generated interesting predictions regarding the possibility of finding new ways to control glutamate receptor function. Together with the recently reported control of the receptors by transmembrane proteins, there is now a whole set of potential regulators of these important families of receptors.

Ionotropic glutamate receptors in GtoPdb v.2021.3

IUPHAR/BPS Guide to Pharmacology CITE, 2021

The ionotropic glutamate receptors comprise members of the NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [35, 92, 155]. Receptor heterogeneity within each class arises from the homo-oligomeric, or hetero-oligomeric, assembly of distinct subunits into cation-selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), 3 TM domains (M1, M3 and M4), a channel lining re-entrant 'p-loop' (M2) located between M1 and M3 and an intracellular carboxy- terminal domain (CTD) [99, 68, 107, 155, 82]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2- see below) has recently been solved at 3.6Å resolution [143] and although providing the most complete structural information current available may not representative of the subunit a...

[Structural characteristics of ionotropic glutamate receptors revealed by channel blockade]

Rossiĭskii fiziologicheskiĭ zhurnal imeni I.M. Sechenova / Rossiĭskaia akademiia nauk

Glutamate is far from the only (in terms of the number of synapses at which it acts) neurotransmitter in the nervous systems of vertebrates and invertebrates. Transmission of excitatory stimuli in the brains of vertebrates and in the neuromuscular system of arthropods is mediated by activation of postsynaptic glutamate receptors of the ionotropic type, i.e., receptors which are ligand-controlled ion channels. The interaction of glutamate with the recognition site on the extracellular side of the receptor converts the channel, for a short period of time, into the open state, this being the basis of the generation of the excitatory postsynaptic potential.

Genetic analysis of neuronal ionotropic glutamate receptor subunits

The Journal of …, 2011

In the brain, fast, excitatory synaptic transmission occurs primarily through AMPA-and NMDA-type ionotropic glutamate receptors. These receptors are composed of subunit proteins that determine their biophysical properties and trafficking behaviour. Therefore, determining the function of these subunits and receptor subunit composition is essential for understanding the physiological properties of synaptic transmission. Here, we discuss and evaluate various genetic approaches that have been used to study AMPA and NMDA receptor subunits. These approaches have demonstrated that the GluA1 AMPA receptor subunit is required for activity-dependent trafficking and contributes to basal synaptic transmission, while the GluA2 subunit regulates Ca 2+ permeability, homeostasis and trafficking to the synapse under basal conditions. In contrast, the GluN2A and GluN2B NMDA receptor subunits regulate synaptic AMPA receptor content, both during synaptic development and plasticity. Ongoing research in this field is focusing on the molecular interactions and mechanisms that control these functions. To accomplish this, molecular replacement techniques are being used, where native subunits are replaced with receptors containing targeted mutations. In this review, we discuss a single-cell molecular replacement approach which should arguably advance our physiological understanding of ionotropic glutamate receptor subunits, but is generally applicable to study of any neuronal protein.

Structural characteristics of ionotropic glutamate receptors as identified by channel blockade

2002

Glutamate is far from the only (in terms of the number of synapses at which it acts) neurotransmitter in the nervous systems of vertebrates and invertebrates. Transmission of excitatory stimuli in the brains of vertebrates and in the neuromuscular system of arthropods is mediated by activation of postsynaptic glutamate receptors of the ionotropic type, i.e., receptors which are ligand-controlled ion channels. The interaction of glutamate with the recognition site on the extracellular side of the receptor converts the channel, for a short period of time, into the open state, this being the basis of the generation of the excitatory postsynaptic potential.

Hodgkin–Huxley–Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif

The Journal of Physiology, 2020

Glutamate receptors are essential ligand‐gated ion channels in the central nervous system that mediate excitatory synaptic transmission in response to the release of glutamate from presynaptic terminals. The structural and biophysical basis underlying the function of these receptors has been studied for decades by a wide range of approaches. However recent structural, pharmacological and genetic studies have provided new insight into the regions of this protein that are critical determinants of receptor function. Lack of variation in specific areas of the protein amino acid sequences in the human population has defined three regions in each receptor subunit that are under selective pressure, which has focused research efforts and driven new hypotheses. In addition, these three closely positioned elements reside near a cavity that is shown by multiple studies to be a likely site of action for allosteric modulators, one of which is currently in use as an FDA‐approved anticonvulsant. T...

Ionotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE, 2019

The ionotropic glutamate receptors comprise members of the NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [34, 87, 147]. Receptor heterogeneity within each class arises from the homo-oligomeric, or hetero-oligomeric, assembly of distinct subunits into cation-selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), three transmembrane domains composed of three membrane spans (M1, M3 and M4), a channel lining re-entrant ‘p-loop’ (M2) located between M1 and M3 and an intracellular carboxy- terminal domain (CTD) [94, 66, 102, 147, 77]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2 – see below) has recently been solved at 3.6Å resolution [135] and although providing the most complete structural information current availabl...