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

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Descending control of pain.

NMDA receptor subunits: Diversity, development and disease

Most excitatory synapses in the brain use the neurotransmitter glutamate to carry impulses between neurons. During fast transmission, glutamate usually activates a mixture of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the postsynaptic cell. Experimental scrutiny of NMDARs provides insight into their involvement in excitatory synaptic transmission and related processes such as as synaptic plasticity, neural development, and pain perception. There is increasing awareness that subtle variation in NMDAR properties is imparted by specific receptor subunits, and recent studies have started to provide perspective into some of the discrete tasks carried out by individual receptor subtypes.

Role of Distinct NMDA Receptor Subtypes at Central Synapses

There is accumulating evidence to implicate the importance of N-methyl-d-aspartate (NMDA) receptors to the induction and maintenance of central sensitization during pain states. However, NMDA receptors may also mediate peripheral sensitization and visceral pain. NMDA receptors are composed of NR1, N

The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review.

N-methyl-D-aspartate (NMDA) receptors contribute to many brain functions. We studied the effect of forebrain-targeted overexpression of the NMDA receptor subunit NR2B on the response of mice to tissue injury and inflammation. Transgenic mice exhibited prominent NR2B expression and enhanced NMDA receptor-mediated synaptic responses in two pain-related forebrain areas, the anterior cingulate cortex and insular cortex, but not in the spinal cord. Although transgenic and wild type mice were indistinguishable in tests of acute pain, transgenic mice exhibited enhanced responsiveness to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant. Genetic modification of forebrain NMDA receptors can therefore influence pain perception, which suggests that forebrain-selective NMDA receptor antagonists, including NR2B-selective agents, may be useful analgesics for persistent pain.

Genetic enhancement of inflammatory pain by forebrain NR2B overexpression.

https://www.cell.com/neuron/pdf/S0896-6273(01)00479-2.pdf

Direct Presynaptic Regulation of GABA/Glycine Release by Kainate Receptors in the Dorsal Horn: An Ionotropic Mechanism

Glutamate is the major fast excitatory transmitter in the central nervous system While normal synaptic transmission is mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, N-methyl-D-aspartate (NMDA) receptors are thought to selectively contribute to plasticity Genetically enhancing NMDA receptor functions enhances animal behav- ior in normal physiological learning and enhances their sensitivity in the case of tissue injury One major mechanism for NMDA receptors is synaptic long-term potentiation (LTP) Here we present evidence that NMDA receptors not only contribute to normal synaptic responses induced by stimulation of local layer V or white matters, but also contribute to generation of action potentials induced by a depolarizing step applied to the soma Calcium-calmodulin sensitive adenylyl cyclase 1 and cAMP signal pathways likely mediate these effects Considering the importance of cingulate neurons in nociception and pain, our results provide a new mechanism for NMDA receptor contributing to neuronal synaptic transmission, spiking properties in forebrains, and possible forebrain-related behavioral nociceptive responses and pain

Forebrain NMDA receptors contribute to neuronal spike responses in adult mice.

TO THE EDITOR—Whereas Wei and colleagues in a recent Nature Neuroscience article1 claim that overexpression of the NMDA receptor subunit NR2B in the forebrain leads to an enhancement of inflammatory pain, the data presented do not necessarily warrant such a claim; instead, the data may suggest that these transgenic mice are better at remembering painful events, and that they learn how to detect certain cues for avoiding potential new injury. First, these authors did not find any alteration in pain sensitivity and nociceptive threshold in transgenic mice in three types of measurements (tail-flicker test, hot-plate test and cold-plate test). These findings are consistent with data from our laboratory2 that these mice exhibited indistinguishable responses to mild foot shock, therefore suggesting that NR2B mice have a normal pain sensitivity and threshold. Second, the authors examined formalin-injection-induced responses in mice. Injection of 5% formalin produced indistinguishable responses (licking) in both phase I (initial 10 minutes) and phase II (10–55 minutes), but with more behavioral response at phase III (55–120 minutes). However, judging from their Fig. 6a, it seems that the NR2B transgenic and wild-type mice exhibited a similar degree of residual licking responses in the second half of phase III (between 90–120 minutes). This suggests that the transgenic mice did not feel differently than the wild type mice at this late stage, thus providing unfavorable evidence to the authors’ own conclusion that raises doubts about the conclusion that the transgenic mice suffered more inflammatory chronic pain. Finally, experiments using mechanical non-noxious stimuli may represent a good indication that these transgenic mice are indeed better learners. Typically non-painful, mechanical poking of von Frey fiber to the dorsum of a hind paw elicited no response in animals. However, at one or three days after complete Freund’s adjuvant (CFA) injection to the hind paw, wild-type animals responded to the stimulation of the injected (ipsilateral) hind paw, but not much to the contralateral (un-injected) hind paw. With the same protocol, NR2B mice Moreover, our recent study has demonstrated that the activation of NMDA receptors in CA1 neurons is necessary for converting short-term memories into long-term memories3. Therefore, it seems that the behavioral responses reported by Wei and colleagues may be due to the enhanced learning and memory capacity in NR2B mice. Furthermore, their results nicely extended our original finding that these mice are better in learning and memory regardless of whether experiences are pleasant or unpleasant. In fact, remembering bad experiences should be evolutionarily meaningful so that animals can avoid harmful situations or predators, thus increasing their survival.

Guo-Du Wang

Papers

Genetic enhancement of inflammatory pain by forebrain NR2B overexpression.

Direct Presynaptic Regulation of GABA/Glycine Release by Kainate Receptors in the Dorsal Horn: An Ionotropic Mechanism

Forebrain NMDA receptors contribute to neuronal spike responses in adult mice.

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