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.

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Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Ionotropic glutamate receptors are composed of homomeric or heteromeric configurations of glutamate receptor subunits. We have cloned a member of a novel class of the rat ionotropic glutamate receptor family, termed chi-1. This subunit exhibits an average identity of 27% to NMDA subunits and 23% to non-NMDA subunits. Regional transcript levels of chi-1 are elevated just prior to and during the first postnatal week, with the highest levels present in the spinal cord, brainstem, hypothalamus, thalamus, CA1 field of the hippocampus, and amygdala. The spatial distribution of chi-1 expression is similar from postnatal day 1 (P1) to adulthood. However, transcript levels decline sharply between P7 and P14 and remain attenuated into adulthood. Functional expression studies in Xenopus oocytes injected with in vitro transcribed chi-1 RNA did not demonstrate agonist-activated currents. Pairwise expression of chi-1 with members of the AMPA, KA, or delta class of glutamate recepto subunits either failed to generate agonist-activated currents or failed to alter the underlying current generated by the coexpressed subunit. However, coexpression of chi-1 with subunits forming otherwise functional NMDA receptors resulted in an inhibition of current responses. Since chi-1 did not alter the currents generated by non-NMDA subunits, this suggests that chi-1 may specifically interact with NMDA receptor subunits. Further characterization will be required to establish the precise role of this glutamate receptor subunit in neuronal signaling.

https://www.jneurosci.org/content/jneuro/15/10/6498.full.pdf

Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family

The role of excitotoxicity in neurodegenerative disease: implications for therapy.

(S)NO signals: translocation, regulation, and a consensus motif.

The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) serves critical functions in physiological and pathological processes in the central nervous system, including neuronal development, plasticity and neurodegeneration. Conventional heteromeric NMDARs composed of NR1 and NR2A-D subunits require dual agonists, glutamate and glycine, for activation. They are also highly permeable to Ca2+, and exhibit voltage-dependent inhibition by Mg2+. Coexpression of NR3A with NR1 and NR2 subunits modulates NMDAR activity. Here we report the cloning and characterization of the final member of the NMDAR family, NR3B, which shares high sequence homology with NR3A. From in situ and immunocytochemical analyses, NR3B is expressed predominantly in motor neurons, whereas NR3A is more widely distributed. Remarkably, when co-expressed in Xenopus oocytes, NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA, and inhibited by D-serine, a co-activator of conventional NMDARs. Moreover, NR1/NR3A or -3B receptors form relatively Ca2+-impermeable cation channels that are resistant to Mg2+, MK-801, memantine and competitive antagonists. In cerebrocortical neurons containing NR3 family members, glycine triggers a burst of firing, and membrane patches manifest glycine-responsive single channels that are suppressible by D-serine. By itself, glycine is normally thought of as an inhibitory neurotransmitter. In contrast, these NR1/NR3A or -3B 'NMDARs' constitute a type of excitatory glycine receptor.

Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits

A novel NMDA receptor-like (NMDAR-L) cDNA was isolated that contained an open reading frame coding for a predicted polypeptide of 1115 amino acids that shares approximately 27% identity with NMDA receptor subunits. In situ hybridization experiments indicated that NMDAR-L mRNA was expressed in the developing rodent CNS. On postnatal day 1 (P1), NMDAR-L mRNA expression was pronounced in the entorhinal cortex, the subiculum and the thalamus, in layer V of the developing neocortex, in the superior and inferior colliculi, and various regions of the hindbrain, excluding the cerebellum. On P5, NMDAR-L mRNA was expressed in layer V of the neocortex, in the entorhinal cortex, in the subiculum, and in the thalamus. On P14, NMDAR-L mRNA was expressed in layers II-VI of the neocortex, in the entorhinal and piriform cortex, in the subiculum and CA1 field, and in the nucleus of the lateral olfactory tract. In the adult brain, NMDAR-L mRNA was detected predominately in the nucleus of the lateral olfactory tract. Injection of NMDAR-L cRNA into Xenopus oocytes did not lead to the expression of homomeric glutamate-activated channels. However, coinjection of the triple combination of NMDAR-L with NMDAR1 and NMDAR2B cRNAs led to a striking decrease in the current magnitude compared to currents obtained after coexpression of the double combination of NMDAR1 with NMDAR2B. While the function of NMDAR-L remains to be established, its developmental and regional expression pattern suggests that NMDAR-L may influence axonal outgrowth and synaptogenesis during brain development.

https://www.jneurosci.org/content/jneuro/15/10/6509.full.pdf

MK Wu

Papers

Developmental and regional expression pattern of a novel NMDA receptor- like subunit (NMDAR-L) in the rodent brain