II. Excitatory amino acid receptors in the brain-gut axis

2001 ◽  
Vol 280 (6) ◽  
pp. G1055-G1060 ◽  
Author(s):  
Pamela J. Hornby
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Excitatory Amino Acid ◽  
Motor Pattern ◽  
Pattern Generation ◽  
Gut Contents ◽  
Dorsal Vagal Complex ◽  
Gastric Accommodation ◽  
Metabotropic Glutamate ◽  
Therapeutic Benefits ◽  
The Brain

In the last decade, there has been a dramatic increase in academic and pharmaceutical interest in central integration of vago-vagal reflexes controlling the gastrointestinal tract. Associated with this, there have been substantial efforts to determine the receptor-mediated events in the dorsal vagal complex that underlie the physiological responses to distension or variations in the composition of the gut contents. Strong evidence supports the idea that glutamate is a transmitter in afferent vagal fibers conveying information from the gut to the brain, and the implications of this are discussed in this themes article. Furthermore, both ionotropic and metabotropic glutamate receptors mediate pre- and postsynaptic control of glutamate transmission related to several reflexes, including swallowing motor pattern generation, gastric accommodation, and emesis. The emphasis of this themes article is on the potential therapeutic benefits afforded by modulation of these receptors at the site of the dorsal vagal complex.

The role of neuroglial metabotropic glutamate receptors in Alzheimer's disease

2021 ◽  
Vol 19 ◽  
Author(s):  
Khaled S. Abd-Elrahman ◽  
Shaarika Sarasija ◽  
Stephen S. G. Ferguson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Expression Patterns ◽  
Neuronal Cell ◽  
Hyperphosphorylated Tau ◽  
Metabotropic Glutamate ◽  
Group I ◽  
The Brain

: Glutamate, the major excitatory neurotramitter in the brain exerts its effects via both ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). There are three subgroups of mGluRs, pre-synaptic Group II and Group III mGluRs and post-synaptic Group I mGluRs. mGluRs are ubiquitously expressed in the brain and their activation is poised upstream of a myriad of signaling pathways, resulting in their implication in the pathogenesis of various neurodegenerative diseases including, Alzheimer’s disease (AD). While the exact mechanism of AD etiology remains elusive, β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles remain the histopathological hallmarks of AD. Though less electrically excitable, neuroglia are a major non-neuronal cell type in the brain and are composed of astrocytes, microglia, and oligodendrocytes. Astrocytes, microglia, and oligodendrocytes provide structural and metabolic support, active immune defence, and axonal support and sheathing, respectively. Interestingly, Aβ and hyperphosphorylated tau are known to disrupt the neuroglial homeostasis in the brain, pushing them towards a more neurotoxic state. In this review, we discuss what is currently known regarding the expression patterns of various mGluRs in neuroglia and how Aβ and tau alter the normal mGluR function in the neuroglia and contribute to the pathophysiology of AD.

Group I Metabotropic Glutamate Receptors Mediate an Inward Current in Rat Substantia Nigra Dopamine Neurons That Is Independent From Calcium Mobilization

1999 ◽  
Vol 82 (4) ◽  
pp. 1974-1981 ◽  
Author(s):  
Ezia Guatteo ◽  
Nicola B. Mercuri ◽  
Giorgio Bernardi ◽  
Thomas Knöpfel
Keyword(s):  
Substantia Nigra ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Excitatory Amino Acid ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Inward Current ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Rat Substantia Nigra

Metabotropic glutamate receptors modulate neuronal excitability via a multitude of mechanisms, and they have been implicated in the pathogenesis of neurodegenerative processes. Here we investigated the responses mediated by group I metabotropic glutamate receptors (mGluRs) in dopamine neurons of the rat substantia nigra pars compacta, using whole cell patch-clamp recordings in combination with microfluorometric measurements of [Ca2+]i and [Na+]i. The selective group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) was bath-applied (20 μM, 30 s to 2 min) or applied locally by means of short-lasting (2–4 s) pressure pulses, delivered through an agonist-containing pipette positioned close to the cell body of the neuron. 3,5-DHPG evoked an inward current characterized by a transient and a sustained component, the latter of which was uncovered only with long-lasting agonist applications. The fast component coincided with a transient elevation of [Ca2+]i, whereas the total current was associated with a rise in [Na+]i. These responses were not affected either by the superfusion of ionotropic excitatory amino acid antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and d-2-amino-5-phosphono-pentanoic acid (d-APV), nor by the sodium channel blocker tetrodotoxin (TTX). (S)-α-methyl-4-carboxyphenylglycine (S-MCPG) and the more selective mGluR1 antagonist 7(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate (CPCCOEt) depressed both 3,5-DHPG–induced inward current components and, although less effectively, the associated [Ca2+]i elevations. On repeated agonist applications the inward current and the calcium transients both desensitized. The time constant of recovery from desensitization differed significantly between these two responses, being 67.4 ± 4.4 s for the inward current and 28.6 ± 2.7 s for the calcium response. Bathing the tissue in a calcium-free/EGTA medium or adding thapsigargin (1 μM) to the extracellular medium prevented the generation of the [Ca2+]i transient, but did not prevent the activation of the inward current. These electrophysiological and fluorometric results show that the 3,5-DHPG–induced inward current and the [Ca2+]i elevations are mediated by independent pathways downstream the activation of mGluR1.

scholarly journals Positive and Negative Coupling of the Metabotropic Glutamate Receptors to a G Protein–activated K+ Channel, GIRK, in Xenopus Oocytes

1997 ◽  
Vol 109 (4) ◽  
pp. 477-490 ◽  
Author(s):  
Dahlia Sharon ◽  
Dmitry Vorobiov ◽  
Nathan Dascal
Keyword(s):  
Protein Kinase ◽  
Glutamate Receptors ◽  
G Protein ◽  
G Proteins ◽  
Metabotropic Glutamate Receptors ◽  
Xenopus Oocytes ◽  
K Channel ◽  
Metabotropic Glutamate ◽  
Girk Channel ◽  
The Brain

Metabotropic glutamate receptors (mGluRs) control intracellular signaling cascades through activation of G proteins. The inwardly rectifying K+ channel, GIRK, is activated by the βγ subunits of Gi proteins and is widely expressed in the brain. We investigated whether an interaction between mGluRs and GIRK is possible, using Xenopus oocytes expressing mGluRs and a cardiac/brain subunit of GIRK, GIRK1, with or without another brain subunit, GIRK2. mGluRs known to inhibit adenylyl cyclase (types 2, 3, 4, 6, and 7) activated the GIRK channel. The strongest response was observed with mGluR2; it was inhibited by pertussis toxin (PTX). This is consistent with the activation of GIRK by Gi/Go-coupled receptors. In contrast, mGluR1a and mGluR5 receptors known to activate phospholipase C, presumably via G proteins of the Gq class, inhibited the channel's activity. The inhibition was preceded by an initial weak activation, which was more prominent at higher levels of mGluR1a expression. The inhibition of GIRK activity by mGluR1a was suppressed by a broad-specificity protein kinase inhibitor, staurosporine, and by a specific protein kinase C (PKC) inhibitor, bis-indolylmaleimide, but not by PTX, Ca2+ chelation, or calphostin C. Thus, mGluR1a inhibits the GIRK channel primarily via a pathway involving activation of a PTX-insensitive G protein and, eventually, of a subtype of PKC, possibly PKC-μ. In contrast, the initial activation of GIRK1 caused by mGluR1a was suppressed by PTX but not by the protein kinase inhibitors. Thus, this activation probably results from a promiscuous coupling of mGluR1a to a Gi/Go protein. The observed modulations may be involved in the mGluRs' effects on neuronal excitability in the brain. Inhibition of GIRK by phospholipase C–activating mGluRs bears upon the problem of specificity of G protein (GIRK interaction) helping to explain why receptors coupled to Gq are inefficient in activating GIRK.

scholarly journals Activity-Dependent Activation of Presynaptic Metabotropic Glutamate Receptors in Locus Coeruleus

2000 ◽  
Vol 83 (3) ◽  
pp. 1141-1149 ◽  
Author(s):  
G. R. Dubé ◽  
K. C. Marshall
Keyword(s):  
Dicarboxylic Acid ◽  
Locus Coeruleus ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Excitatory Amino Acid ◽  
Synaptic Activity ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group Ii ◽  
Activity Dependent

Synaptic activation of metabotropic glutamate receptors (mGluRs) in the locus coeruleus (LC) was investigated in adult rat brain slice preparations. Evoked excitatory postsynaptic potentials (EPSPs) resulting from stimulation of LC afferents were measured with current clamp from intracellularly recorded LC neurons. In this preparation, mGluR agonists (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid ( t-ACPD) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4) activate distinct presynaptic mGluRs, resulting in an inhibition of EPSPs. When two stimuli were applied to afferents at intervals >200 ms, the amplitude of the second [test (T)] EPSP was identical in amplitude to the first [control(C)]. However, when a stimulation volley was delivered before T, the amplitude of the latter EPSP was consistently smaller than C. The activity-dependent depression (ADD) was dependent on the frequency and duration of the train and the interval between the train and T. ADD was potentiated in the presence of an excitatory amino acid (EAA) uptake inhibitorL- trans-pyrrolidine-2,4-dicarboxylic acid ( t-PDC, 100 μM), changing the T/C ratio from 0.84 ± 0.05 (mean ± SE) in control to 0.69 ± 0.04 in t-PDC ( n = 9). In the presence of t-PDC, the depolarizing response of LC neurons to focally applied glutamate was also increased. Together, these results suggest that accumulation of EAA after synaptic stimulation may be responsible for ADD. To test if ADD is a result of the activation of presynaptic mGluRs, the effect of selective mGluR antagonists on ADD was assessed. In the presence of t-PDC, bath applied (S)-amino-2-methyl-4-phosphonobutanoic acid (MAP4, 500 μM), a mGluR group III antagonist, significantly reversed the decrease in T/C ratio after a train stimulation [from 0.66 ± 0.04 to 0.81 ± 0.02 (mean ± SE), n = 5]. The T/C ratio in the presence of MAP4 was not different from that measured in the absence of a stimulation volley. Conversely, ethyl glutamic acid (EGLU, 500 μM), a mGluR group II antagonist, failed to alter the T/C ratio. Together, these results suggest that, in LC, group III presynaptic mGluR activation provides a feedback mechanism by which excitatory synaptic transmission can be negatively modulated during high-frequency synaptic activity. Furthermore, this study provides functional differentiation between presynaptic groups II and III mGluR in LC and suggests that the group II mGluR may be involved in functions distinct from those of group III mGluRs.

scholarly journals Adenosine and Metabotropic Glutamate Receptors Are Present in Blood Serum and Exosomes from SAMP8 Mice: Modulation by Aging and Resveratrol

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1628
Author(s):  
Alejandro Sánchez-Melgar ◽  
José Luis Albasanz ◽  
Christian Griñán-Ferré ◽  
Mercè Pallàs ◽  
Mairena Martín
Keyword(s):  
Blood Serum ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate ◽  
A2a Receptors ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Samp8 Mice ◽  
G Protein Coupled ◽  
The Brain

Adenosine (ARs) and metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors (GPCRs) that are modulated in the brain of SAMP8 mice, an animal model of Alzheimer’s disease (AD). In the present work, it is shown the presence of ARs and mGluRs in blood serum and derived exosomes from SAMP8 mice as well as its possible modulation by aging and resveratrol (RSV) consumption. In blood serum, adenosine A1 and A2A receptors remained unaltered from 5 to 7 months of age. However, an age-related decrease in adenosine level was observed, while 5′-Nucleotidase activity was not modulated. Regarding the glutamatergic system, it was observed a decrease in mGluR5 density and glutamate levels in older mice. In addition, dietary RSV supplementation caused an age-dependent modulation in both adenosinergic and glutamatergic systems. These GPCRs were also found in blood serum-derived exosomes, which might suggest that these receptors could be released into circulation via exosomes. Interestingly, changes elicited by age and RSV supplementation on mGluR5 density, and adenosine and glutamate levels were similar to that detected in whole-brain. Therefore, we might suggest that the quantification of these receptors, and their corresponding endogenous ligands, in blood serum could have predictive value for early diagnosis in combination with other distinctive hallmarks of AD.

Slow excitatory amino acid receptor-mediated synaptic transmission in turtle cerebellar Purkinje cells

1990 ◽  
Vol 63 (3) ◽  
pp. 637-650 ◽  
Author(s):  
L. J. Larson-Prior ◽  
D. R. McCrimmon ◽  
N. T. Slater
Keyword(s):  
Amino Acid ◽  
Purkinje Cells ◽  
Excitatory Amino Acid ◽  
Motor Pattern ◽  
Pattern Generation ◽  
Resting Membrane Potential ◽  
Excitatory Amino Acid Receptor ◽  
Acid Receptor ◽  
Synaptic Potentials ◽  
Cerebellar Purkinje Cells

1. The excitatory synaptic responses of turtle Purkinje cells to climbing and parallel fiber (CF and PF) stimulation have been studied by the use of intrasomatic and intradendritic recordings in intact cerebellum and brain stem-cerebellum preparations in vitro. 2. Activation of CF inputs from the cerebellar peduncle or the region of the inferior olive evoked complex spikes followed by slow excitatory postsynaptic potentials (EPSPs), both of which were evoked in an all-or-none fashion. 3. Single stimuli applied to the cerebellar molecular layer activated fast PF-mediated EPSPs; brief trains of PF stimuli (2-5 stimuli, 50-100 Hz) evoked volleys of fast EPSPs followed by a slow, long-lasting EPSP. The amplitude of the fast and slow PF-mediated EPSPs were both graded with stimulus intensity. 4. Slow EPSPs evoked both by CF and PF stimulation were associated with an increase in membrane conductance and were increased in amplitude by hyperpolarization. 5. The CF-evoked slow EPSP was profoundly attenuated by repetitive activation at interstimulus intervals of less than 15-20 s, whereas the PF-evoked slow EPSP was not reduced by repetitive activation. 6. The PF-evoked slow EPSP readily triggered dendritic pacemaker discharges when activated at or near resting membrane potential. The activation of this potential by phasic PF volleys may, therefore, provide an appropriate synaptic drive to cerebellar Purkinje cells to entrain the intrinsic pacemaker properties of these cells to cycles of motor activity. 7. Both slow synaptic potentials were blocked by the excitatory amino acid antagonists kynurenate and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but not by DL-2-amino-5-phosphonovalerate (DL-AP5) or L-serine-O-phosphate (L-SOP). The PF-evoked slow EPSP was selectively antagonized by L-2-amino-4-phosphonobutyrate (L-AP4; 20-100 microM). 8. It is suggested that the CF- and PF-evoked slow EPSPs observed in this study represent a novel class of excitatory amino acid receptor-mediated slow synaptic potentials activated by Purkinje cell afferents, which may play a role in synaptic integration and motor pattern generation in the cerebellum.

scholarly journals Acetylation-dependent glutamate receptor GluR signalosome formation for STAT3 activation in both transcriptional and metabolism regulation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiang-Rong Li ◽  
Xiaju Cheng ◽  
Jia Sun ◽  
Yan S. Xu ◽  
Nannan Chen ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Lysyl Oxidase ◽  
Critical Role ◽  
Creb Binding Protein ◽  
Metabotropic Glutamate ◽  
Metabolism Regulation ◽  
Cancer Initiation ◽  
Transcription 3 ◽  
The Brain

AbstractBesides their original regulating roles in the brain, spinal cord, retina, and peripheral nervous system for mediating fast excitatory synaptic transmission, glutamate receptors consisting of metabotropic glutamate receptors (GluRs) and ionotropic glutamate receptors (iGluRs) have emerged to have a critical role in the biology of cancer initiation, progression, and metastasis. However, the precise mechanism underpinning the signal transduction mediated by ligand-bound GluRs is not clearly elucidated. Here, we show that iGluRs, GluR1 and GluR2, are acetylated by acetyltransferase CREB-binding protein upon glutamate stimulation of cells, and are targeted by lysyl oxidase-like 2 for deacetylation. Acetylated GluR1/2 recruit β-arrestin1/2 and signal transducer and activator of transcription 3 (STAT3) to form a protein complex. Both β-arrestin1/2 and STAT3 are subsequently acetylated and activated. Simultaneously, activated STAT3 acetylated at lysine 685 translocates to mitochondria to upregulate energy metabolism-related gene transcription. Our results reveal that acetylation-dependent formation of GluR1/2–β-arrestin1/2–STAT3 signalosome is critical for glutamate-induced cell proliferation.

scholarly journals Imaging fictive locomotor patterns in larval Drosophila

2015 ◽  
Vol 114 (5) ◽  
pp. 2564-2577 ◽  
Author(s):  
Stefan R. Pulver ◽  
Timothy G. Bayley ◽  
Adam L. Taylor ◽  
Jimena Berni ◽  
Michael Bate ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Imaging Techniques ◽  
Motor Pattern ◽  
Pattern Generation ◽  
Motor Patterns ◽  
Posterior Direction ◽  
Muscle Groups ◽  
Locomotor Patterns ◽  
Left Right Asymmetry ◽  
The Brain

We have established a preparation in larval Drosophila to monitor fictive locomotion simultaneously across abdominal and thoracic segments of the isolated CNS with genetically encoded Ca2+ indicators. The Ca2+ signals closely followed spiking activity measured electrophysiologically in nerve roots. Three motor patterns are analyzed. Two comprise waves of Ca2+ signals that progress along the longitudinal body axis in a posterior-to-anterior or anterior-to-posterior direction. These waves had statistically indistinguishable intersegmental phase delays compared with segmental contractions during forward and backward crawling behavior, despite being ∼10 times slower. During these waves, motor neurons of the dorsal longitudinal and transverse muscles were active in the same order as the muscle groups are recruited during crawling behavior. A third fictive motor pattern exhibits a left-right asymmetry across segments and bears similarities with turning behavior in intact larvae, occurring equally frequently and involving asymmetry in the same segments. Ablation of the segments in which forward and backward waves of Ca2+ signals were normally initiated did not eliminate production of Ca2+ waves. When the brain and subesophageal ganglion (SOG) were removed, the remaining ganglia retained the ability to produce both forward and backward waves of motor activity, although the speed and frequency of waves changed. Bilateral asymmetry of activity was reduced when the brain was removed and abolished when the SOG was removed. This work paves the way to studying the neural and genetic underpinnings of segmentally coordinated motor pattern generation in Drosophila with imaging techniques.

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