Structure and trafficking of NMDA and GABAA receptors

2006 ◽  
Vol 34 (5) ◽  
pp. 877-881 ◽  
Author(s):  
F.A. Stephenson
Keyword(s):  
Nmda Receptor ◽  
Cell Surface ◽  
Nmda Receptors ◽  
Gabaa Receptors ◽  
Synaptic Function ◽  
Molecular Organization ◽  
Cell Surface Expression ◽  
Inhibitory Synapses ◽  
Receptor Subtype ◽  
Receptor Complexes

The fidelity of synaptic function is dependent on the expression of the appropriate neurotransmitter receptor subtype, the targeting and trafficking of receptors to synapses as well as the regulation of the actual number of receptors at synapses. GABAA (γ-aminobutyric acid type A) receptors and NMDA (N-methyl-D-aspartate) receptors are both examples of ligand-gated, heteromeric neurotransmitter receptors whose cell-surface expression is dynamic and tightly regulated. NMDA receptors are localized at excitatory synapses. These synapses are highly structured but dynamic, with the interplay between NMDA receptors and NMDA receptor-associated scaffolding proteins regulating the expression of functional cell-surface synaptic and extrasynaptic receptors. Based on current information, inhibitory synapses seem to be less ordered, and a GABAA receptor equivalent of PSD-95 (postsynaptic density-95), the scaffolding molecule pivotal to the organization of NMDA receptor complexes at synapses, is yet to be validated. In the present paper, processes regulating the trafficking, assembly and molecular organization of both NMDA receptors and GABAA receptors will be discussed.

scholarly journals Structure, function, and allosteric modulation of NMDA receptors

2018 ◽  
Vol 150 (8) ◽  
pp. 1081-1105 ◽  
Author(s):  
Kasper B. Hansen ◽  
Feng Yi ◽  
Riley E. Perszyk ◽  
Hiro Furukawa ◽  
Lonnie P. Wollmuth ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Structural Features ◽  
Synaptic Function ◽  
Genomic Variation ◽  
Receptor Subtypes ◽  
Receptor Complexes ◽  
The Central Nervous System ◽  
Excitatory Neurotransmission ◽  
And Function

NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.

scholarly journals N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Rafael Rivas-Santisteban ◽  
Alejandro Lillo ◽  
Jaume Lillo ◽  
Joan-Biel Rebassa ◽  
Joan S. Contestí ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmda Receptor ◽  
Transgenic Mice ◽  
Nmda Receptors ◽  
Mapk Pathway ◽  
Primary Cultures ◽  
Brain Slices ◽  
Receptor Complexes ◽  
Receptor Heteromers

Abstract Background The cannabinoid CB2 receptor (CB2R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of current medication in Alzheimer’s disease patients and with the aim of finding neuromodulators of their actions that could provide benefits in dementia, we hypothesized that cannabinoids could modulate NMDA function. Methods Immunocytochemistry was used to analyze the colocalization between CB2 and NMDA receptors; bioluminescence resonance energy transfer was used to detect CB2-NMDA receptor complexes. Calcium and cAMP determination, mitogen-activated protein kinase (MAPK) pathway activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify CB2-NMDA heteromer expression in mouse primary cultures and in the brain of APPSw/Ind transgenic mice, an Alzheimer’s disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP). Results In a heterologous system, we identified CB2-NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon-γ. CB2R activation blunted NMDA receptor-mediated signaling in primary hippocampal neurons from APPSw/Ind mice. Furthermore, imaging studies showed that in brain slices and in primary cells (microglia or neurons) from APPSw/Ind mice, there was a marked overexpression of macromolecular CB2-NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input by cannabinoids. Conclusions The results indicate a negative cross-talk in CB2-NMDA complexes signaling. The expression of the CB2-NMDA receptor heteromers increases in both microglia and neurons from the APPSw/Ind transgenic mice, compared with levels in samples from age-matched control mice.

scholarly journals Importance of N-glycosylation positioning for cell-surface expression, targeting, affinity and quality control of the human AT1 receptor

2005 ◽  
Vol 390 (1) ◽  
pp. 367-376 ◽  
Author(s):  
Pascal M. Lanctot ◽  
Patrice C. Leclerc ◽  
Martin Clément ◽  
Mannix Auger-Messier ◽  
Emanuel Escher ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Surface ◽  
Functional Expression ◽  
Surface Expression ◽  
Glycosylation Site ◽  
At1 Receptor ◽  
Cell Surface Expression ◽  
Receptor Subtype ◽  
Angiotensin Ii Receptor ◽  
Glycosylation Sites

GPCRs (G-protein-coupled receptors) are preferentially N-glycosylated on ECL2 (extracellular loop 2). We previously showed that N-glycosylation of ECL2 was crucial for cell-surface expression of the hAT1 receptor (human angiotensin II receptor subtype 1). Here, we ask whether positioning of the N-glycosylation sites within the various ECLs of the receptor is a vital determinant in the functional expression of hAT1 receptor at the cell surface. Artificial N-glycosylation sequons (Asn-Xaa-Ser/Thr) were engineered into ECL1, ECL2 and ECL3. N-glycosylation of ECL1 caused a very significant decrease in affinity and cell surface expression of the resulting receptor. Shifting the position of the ECL2 glycosylation site by two residues led to the synthesis of a misfolded receptor which, nevertheless, was trafficked to the cell surface. The misfolded nature of this receptor is supported by an increased interaction with the chaperone HSP70 (heat-shock protein 70). Introduction of N-glycosylation motifs into ECL3 yielded mutant receptors with normal affinity, but low levels of cell surface expression caused by proteasomal degradation. This behaviour differed from that observed for the aglycosylated receptor, which accumulated in the endoplasmic reticulum. These results show how positioning of the N-glycosylation sites altered many properties of the AT1 receptor, such as targeting, folding, affinity, cell surface expression and quality control.

Opiate and N-methyl-D-aspartate receptors in form-deprivation myopia

1998 ◽  
Vol 15 (6) ◽  
pp. 1089-1096 ◽  
Author(s):  
ANDY J. FISCHER ◽  
RUTH L.P. SELTNER ◽  
WILLIAM K. STELL
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Opiate Receptors ◽  
Plexiform Layer ◽  
Amacrine Cells ◽  
Opiate Receptor ◽  
Receptor Subtype ◽  
Inner Plexiform Layer ◽  
Toxic Dose ◽  
Ocular Growth

Pharmacological studies have implicated retinal opiate pathways in the visual regulation of ocular growth. However, the effects of opiate receptor subtype-specific compounds on form-deprivation myopia (FDM) are inconsistent (Seltner et al., 1997), and may be mediated by non-opiate receptors. The purpose of this study was to test whether opiate receptor-inactive (D-) enantiomers elicit the same FDM-suppressing effect as their opiate receptor-active (L-) counterparts. Since some opiates are thought to act at NMDA receptors, we also tested whether NMDA receptor agonists and antagonists influence ocular growth or FDM. We found that both L- and D- enantiomers of morphine-like compounds (dextrorphanol and levorphanol, and D- and L-naloxone) were equally effective in blocking FDM. The NMDA receptor antagonists dextromethorphan, MK801, and AP5 also suppressed FDM. A single toxic dose of NMDA, that destroys many subtypes of amacrine cells (including those that synthesize the opioid peptide enkephalin), induced myopia and ocular enlargement in ungoggled eyes, and eliminated the ability of form-deprivation to enhance ocular growth. The NR-1 subunit of the NMDA receptor was localized to a narrowly stratified, intense stratum at approximately 50% depth in the inner plexiform layer, diffusely throughout the proximal inner plexiform layer, and to many somata in the amacrine and ganglion cell layers. These observations suggest that most effects of opiate receptor ligands on FDM in the chick are mediated by non-opiate receptors, which are likely to include NMDA receptors. NMDA as an excitotoxin transiently enhances ocular growth, but thereafter disables retinal mechanisms that promote emmetropization and FDM. These observations are consistent with a prominent role for pathways utilizing NMDA receptors in FDM and ocular growth-control.

scholarly journals GABA acts as a ligand chaperone in the early secretory pathway to promote cell surface expression of GABAA receptors

2010 ◽  
Vol 1346 ◽  
pp. 1-13 ◽  
Author(s):  
Randa S. Eshaq ◽  
Letha D. Stahl ◽  
Randolph Stone ◽  
Sheryl S. Smith ◽  
Lucy C. Robinson ◽  
...  
Keyword(s):  
Cell Surface ◽  
Gabaa Receptors ◽  
Secretory Pathway ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Early Secretory Pathway

scholarly journals PGE2 Modulates GABAA Receptors via an EP1 Receptor-Mediated Signaling Pathway

2015 ◽  
Vol 36 (5) ◽  
pp. 1699-1711 ◽  
Author(s):  
Guang Yang ◽  
Wen-Hao Dong ◽  
Chang-Long Hu ◽  
Yan-Ai Mei
Keyword(s):  
Cell Surface ◽  
Western Blot ◽  
Gabaa Receptors ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Granule Neurons ◽  
Patch Clamp Technique ◽  
Mammalian Tissues ◽  
Ep1 Receptor ◽  
Western Blot Data

Aims: PGE2 is one of the most abundant prostanoids in mammalian tissues, but its effect on neuronal receptors has not been well investigated. This study examines the effect of PGE2 on GABAA receptor currents in rat cerebellar granule neurons. Methods: GABAA currents were recorded using a patch-clamp technique. Cell surface and total protein of GABAA β1/2/3 subunits was carried out by Western blot analysis. Results: Upon incubation of neurons with PGE2 (1 µM) for 60 minutes, GABAA currents were significantly potentiated. This PGE2-driven effect could be blocked by PKC or CaMKII inhibitors as well as EP1 receptor antagonist, and mimicked by PMA or EP1 receptor agonist. Furthermore, Western blot data showed that PGE2 did not increase the total expression level of GABAA receptors, but significantly increased surface levels of GABAA β1/2/3 subunits after 1 h of treatment. Consistently, both PKC and CaMKII inhibitors were able to reduce PGE2-induced increases in cell surface expression of GABAA receptors. Conclusion: Activation of either the PKC or CaMKII pathways by EP1 receptors mediates the PGE2-induced increase in GABAA currents. This suggests that upregulation of postsynaptic GABAA receptors by PGE2 may have profound effects on cerebellar functioning under physiological and pathological conditions.

scholarly journals Bidentatide, a Novel Plant Peptide Derived from Achyranthes bidentata Blume: Isolation, Characterization, and Neuroprotection through Inhibition of NR2B-Containing NMDA Receptors

2021 ◽  
Vol 22 (15) ◽  
pp. 7977
Author(s):  
Fei Ding ◽  
Yunpeng Bai ◽  
Qiong Cheng ◽  
Shu Yu ◽  
Mengchun Cheng ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Hippocampal Neurons ◽  
Receptor Subtype ◽  
Achyranthes Bidentata ◽  
Amino Acid Peptide ◽  
Nmda Current ◽  
Neuroprotective Actions ◽  
In Vitro Effects

Increasing attention is being focused on the use of polypeptide-based N-methyl-d-aspartate (NMDA) receptor antagonists for the treatment of nervous system disorders. In our study on Achyranthes bidentata Blume, we identified an NMDA receptor subtype 2B (NR2B) antagonist that exerts distinct neuroprotective actions. This antagonist is a 33 amino acid peptide, named bidentatide, which contains three disulfide bridges that form a cysteine knot motif. We determined the neuroactive potential of bidentatide by evaluating its in vitro effects against NMDA-mediated excitotoxicity. The results showed that pretreating primary cultured hippocampal neurons with bidentatide prevented NMDA-induced cell death and apoptosis via multiple mechanisms that involved intracellular Ca2+ inhibition, NMDA current inhibition, and apoptosis-related protein expression regulation. These mechanisms were all dependent on bidentatide-induced inhibitory regulation of NR2B-containing NMDA receptors; thus, bidentatide may contribute to the development of neuroprotective agents that would likely possess the high selectivity and safety profiles inherent in peptide drugs.

scholarly journals Multiple Receptor Subtypes for the CGRP Super-Family

2001 ◽  
Vol 1 ◽  
pp. 15-15
Author(s):  
R. Quirion ◽  
J.-G. Chabot Chabot ◽  
Y. Dumont
Keyword(s):  
Molecular Data ◽  
Molecular Organization ◽  
Molecular Evidence ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Single Class ◽  
Functional Studies ◽  
Receptor Complexes ◽  
Multiple Receptors

Molecular evidence for the existence of multiple receptors for CGRP has been rather difficult to obtain. Over 10 years after suggesting the existence of at least two classes (CGRP1 and CGRP2) of CGRP receptors on the basis of pharmacological data[1], molecular data on the CGRP2 receptor subtype are still lacking as well as potent and selective antagonists. The situation is somewhat different for the functional CGRP1 subtype which is likely composed of diverse subunits CRLR, RAMP1 and possibly RCP[2]. Moreover, BIBN 4096BS was recently reported as the first nonpeptide highly potent CGRP1 receptor antagonist[3]. However, in situ hybridization and receptor autoradiographic data have clearly shown the existence of major mismatches (e.g., cerebellum) between the discrete localization of CRLR, RAMP1, and specific CGRP binding sites supporting the existence of CGRP receptor subtypes. Functional studies have also provided evidence in that regard (for a recent review: [4]). Accordingly, additional studies aiming at cloning additional CGRP receptors are certainly warranted. Similarly, recent evidence from various laboratories including ours suggests the existence of more than one class (CRLR and RAMP2) of adrenomedullin receptors at least in the rat brain. In contrast, most evidence suggests the existence of a single class of amylin receptors. In brief, it appears that multiple receptors or receptor complexes do exist for CGRP and related peptides but their composition is apparently unique among the GPCR super-family and additional data are needed to fully establish the molecular organization of each subtype. Supported by CIHR of Canada.

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