scholarly journals A modulatory effect of the feedback from higher visual areas to V1 in the mouse

2013 ◽  
Vol 109 (10) ◽  
pp. 2618-2631 ◽  
Author(s):  
Roberto De Pasquale ◽  
S. Murray Sherman
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Layer 4 ◽  
Group I Mglurs ◽  
Group Ii ◽  
Visual Cortical ◽  
Higher Visual Areas ◽  
Brain Slice Preparation ◽  
Feedback Pathway

Using a mouse brain slice preparation, we studied the modulatory effects of a feedback projection from higher visual cortical areas, mostly or exclusively area LM (or V2), on two inputs to layer 4 cells in the first visual area (V1). The two inputs to these cells were geniculocortical and an unspecified intracortical input, possibly involving layer 6 cells. We found that activation of metabotropic glutamate receptors (mGluRs) from stimulation of the feedback projection reduced the evoked excitatory postsynaptic currents of both of these inputs to layer 4 but that this modulation acts in an input-specific way. Reducing the strength of the geniculocortical input in adults involved both presynaptic and postsynaptic group I mGluRs (although in younger animals presynaptic group II mGluRs were also involved), whereas modulation of the intracortical input acted entirely via postsynaptic group II mGluRs. These results demonstrate that one of the effects of this feedback pathway is to control the gain of geniculocortical transmission.

scholarly journals The post-synaptic scaffolding protein tamalin regulates ligand-mediated trafficking of metabotropic glutamate receptors

2020 ◽  
Vol 295 (25) ◽  
pp. 8575-8588
Author(s):  
Saurabh Pandey ◽  
Namrata Ramsakha ◽  
Rohan Sharma ◽  
Ravinder Gulia ◽  
Prachi Ojha ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Protein Trafficking ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Fragile X ◽  
Critical Role ◽  
Scaffolding Protein ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group I Mglurs

Group I metabotropic glutamate receptors (mGluRs) play important roles in various neuronal functions and have also been implicated in multiple neuropsychiatric disorders like fragile X syndrome, autism, and others. mGluR trafficking not only plays important roles in controlling the spatiotemporal localization of these receptors in the cell but also regulates the activity of these receptors. Despite this obvious significance, the cellular machineries that control the trafficking of group I metabotropic glutamate receptors in the central nervous system have not been studied in detail. The post-synaptic scaffolding protein tamalin has been shown to interact with group I mGluRs and also with many other proteins involved in protein trafficking in neurons. Using a molecular replacement approach in mouse hippocampal neurons, we show here that tamalin plays a critical role in the ligand-dependent internalization of mGluR1 and mGluR5, members of the group I mGluR family. Specifically, knockdown of endogenous tamalin inhibited the ligand-dependent internalization of these two receptors. Both N-terminal and C-terminal regions of tamalin played critical roles in mGluR1 endocytosis. Furthermore, we found that tamalin regulates mGluR1 internalization by interacting with S-SCAM, a protein that has been implicated in vesicular trafficking. Finally, we demonstrate that tamalin plays a critical role in mGluR-mediated internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, a process believed to be the cellular correlate for mGluR-dependent synaptic plasticity. Taken together, these findings reveal a mechanistic role of tamalin in the trafficking of group I mGluRs and suggest its physiological implications in the brain.

Groups II and III Metabotropic Glutamate Receptors Differentially Modulate Brief and Prolonged Nociception in Primate STT Cells

2000 ◽  
Vol 84 (6) ◽  
pp. 2998-3009 ◽  
Author(s):  
Volker Neugebauer ◽  
Ping-Sun Chen ◽  
William D. Willis
Keyword(s):  
Glutamate Receptors ◽  
Dorsal Horn ◽  
Central Sensitization ◽  
Metabotropic Glutamate Receptors ◽  
Background Activity ◽  
Mechanical Stimuli ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

The heterogeneous family of G-protein-coupled metabotropic glutamate receptors (mGluRs) provides excitatory and inhibitory controls of synaptic transmission and neuronal excitability in the nervous system. Eight mGluR subtypes have been cloned and are classified in three subgroups. Group I mGluRs can stimulate phosphoinositide hydrolysis and activate protein kinase C whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) mGluRs share the ability to inhibit cAMP formation. The present study examined the roles of groups II and III mGluRs in the processing of brief nociceptive information and capsaicin-induced central sensitization of primate spinothalamic tract (STT) cells in vivo. In 11 anesthetized male monkeys ( Macaca fascicularis), extracellular recordings were made from 21 STT cells in the lumbar dorsal horn. Responses to brief (15 s) cutaneous stimuli of innocuous (brush), marginally and distinctly noxious (press and pinch, respectively) intensity were recorded before, during, and after the infusion of group II and group III mGluR agonists into the dorsal horn by microdialysis. Different concentrations were applied for at least 20 min each (at 5 μl/min) to obtain cumulative concentration-response relationships. Values in this paper refer to the drug concentrations in the microdialysis fibers; actual concentrations in the tissue are about three orders of magnitude lower. The agonists were also applied at 10–25 min after intradermal capsaicin injection. The group II agonists (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (LCCG1, 1 μM-10 mM, n = 6) and (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268; 1 μM-10 mM, n = 6) had no significant effects on the responses to brief cutaneous mechanical stimuli (brush, press, pinch) or on ongoing background activity. In contrast, the group III agonist L(+)-2-amino-4-phosphonobutyric acid (LAP4, 0.1 μM-10 mM, n = 6) inhibited the responses to cutaneous mechanical stimuli in a concentration-dependent manner, having a stronger effect on brush responses than on responses to press and pinch. LAP4 did not change background discharges significantly. Intradermal injections of capsaicin increased ongoing background activity and sensitized the STT cells to cutaneous mechanical stimuli (ongoing activity > brush > press > pinch). When given as posttreatment, the group II agonists LCCG1 (100 μM, n = 5) and LY379268 (100 μM, n = 6) and the group III agonist LAP4 (100 μM, n = 6) reversed the capsaicin-induced sensitization. After washout of the agonists, the central sensitization resumed. Our data suggest that, while activation of both group II and group III mGluRs can reverse capsaicin-induced central sensitization, it is the actions of group II mGluRs in particular that undergo significant functional changes during central sensitization because they modulate responses of sensitized STT cells but have no effect under control conditions.

Roles of specific metabotropic glutamate receptor subtypes in regulation of hippocampal CA1 pyramidal cell excitability

1995 ◽  
Vol 74 (1) ◽  
pp. 122-129 ◽  
Author(s):  
R. W. Gereau ◽  
P. J. Conn
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Brain Slices ◽  
Second Messenger ◽  
Receptor Subtypes ◽  
Bhk Cells ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

1. Metabotropic glutamate receptors (mGluRs) are coupled to various second-messenger systems through guanosine 5'-triphosphate-binding proteins. To date, at least seven mGluRs have been cloned, and these mGluR subtypes can be divided into three major groups on the basis of similarities in amino acid sequence, coupling to second-messenger cascades in expression systems, and pharmacological profiles. These groups include group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), and group III (mGluR4, mGluR6, and mGluR7). 2. On the basis of its selective activation of phosphoinositide hydrolysis in brain slices and its ability to activate mGluR1a expressed in Xenopus oocytes, others have suggested that 3.5-dihydroxyphenylglycine (DHPG) may be selective for group I mGluRs. Consistent with this hypothesis, we report that DHPG also activates mGluR5 expressed in oocytes, whereas it is inactive at mGluR4 and mGluR7 expressed in baby hamster kidney (BHK) cells. The compound (2S,1'R,2'R,3'R)-2-(2.3-dicarboxycyclopropyl)glycine (DCG-IV) activates both mGluR2 and mGluR3 at submicromolar concentrations, whereas it is inactive at mGluR4 and mGluR1, suggesting that this compound may be selective for group II mGluRs. Consistent with this hypothesis, we find that DCG-IV does not activate mGluR5 expressed in oocytes and does not activate mGluR7 expressed in BHK cells. These findings suggest that DHPG and DCG-IV are highly selective agonists for group I and group II mGluRs, respectively. 3. Previous studies that have examined the physiological roles of mGluRs have generally used agonists that do not differentiate between the various subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonists reversibly reverse chemical LTD induced by group I, group II and group III metabotropic glutamate receptors

2013 ◽  
Vol 74 ◽  
pp. 135-146 ◽  
Author(s):  
David Lodge ◽  
Patrick Tidball ◽  
Marion S. Mercier ◽  
Sarah J. Lucas ◽  
Lydia Hanna ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

scholarly journals Metabotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Francine Acher ◽  
Giuseppe Battaglia ◽  
Hans Bräuner-Osborne ◽  
P. Jeffrey Conn ◽  
Robert Duvoisin ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
G Protein ◽  
Metabotropic Glutamate Receptors ◽  
Transmembrane Domain ◽  
Acid Group ◽  
Allosteric Modulators ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [334]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu1 and mGlu5), Group-II (mGlu2 and mGlu3) and Group-III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading).Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. The structures of the VFTD of mGlu1, mGlu2, mGlu3, mGlu5 and mGlu7 have been solved [190, 262, 255, 386]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organization similar to that of other GPCRs, although the helices appear more compacted [85, 415, 59]. mGlu form constitutive dimers crosslinked by a disulfide bridge. Recent studies revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [86]. Although well characterized in transfected cells, co-localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain [422, 257]. The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [29] and antagonized by (S)-hexylhomoibotenic acid [223]. Group-II mGlu receptors may be activated by LY389795 [256], LY379268 [256], eglumegad [337, 416], DCG-IV and (2R,3R)-APDC [338], and antagonised by eGlu [161] and LY307452 [408, 100]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [125]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu4, mGlu5, and mGlu7 in the micromolar range [176]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.

Modulation of mEPSCs in Olfactory Bulb Mitral Cells by Metabotropic Glutamate Receptors

1997 ◽  
Vol 78 (3) ◽  
pp. 1468-1475 ◽  
Author(s):  
N. E. Schoppa ◽  
G. L. Westbrook
Keyword(s):  
Olfactory Bulb ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Mitral Cells ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Selective Agonist ◽  
Group I ◽  
Mepsc Frequency ◽  
Group Ii

Schoppa, N. E. and G. L. Westbrook. Modulation of mEPSCs in olfactory bulb mitral cells by metabotropic glutamate receptors. J. Neurophysiol. 78: 1468–1475, 1997. Olfactory bulb mitral cells express group I (mGluR1), group II (mGluR2), and group III (mGluR7 and mGluR8) metabotropic glutamate receptors. We examined the role of these mGluRs on excitatory synaptic transmission in cultured mitral cells with the use of whole cell patch-clamp recordings. The effects of group-selective mGluR agonists and antagonists were tested on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor-mediated miniature excitatory postsynaptic currents (mEPSCs). (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylate (ACPD) or the group-I-selective agonist 3,5-dihydroxyphenylglycine evoked an inward current accompanied by a decrease in membrane conductance, consistent with the previously described closure of potassium channels by group I agonists. The increased cellular excitability was accompanied by an increase in mEPSC frequency in some cells. When calcium entry was blocked by cadmium, ACPD or the group-II-selective agonist 2-(2,3-dicarboxycyclopropyl)-glycine reduced the mEPSC frequency. l-2-amino-4-phosphonobutyric acid (l-AP4), a group-III-selective agonist, caused a similar decrease. The concentration-dependence ofl-AP4-mediated inhibition was most consistent with activation of mGluR8. We investigated two possible effector mechanisms for the group III presynaptic receptor. Bath application of forskolin or 3-isobutyl-1-methylxantine had no effect on mEPSC frequency. Increasing calcium influx by raising extracellular K+ caused a large increase in the mEPSC frequency but did not enhance l-AP4-mediated inhibition. Thus inhibition of mEPSCs involves a mechanism downstream of calcium entry and appears to be independent of adenosine 3′,5′-cyclic monophosphate. Our results indicate that both group II and III receptors can inhibit glutamate release at mitral cell terminals. Although group II/III receptors had a similar effect on mEPSCs, differences in location on nerve terminals and in glutamate sensitivity suggest that each mGluR may have discrete actions on mitral cell activity.

Role of Group I Metabotropic Glutamate Receptors in the Patterning of Epileptiform Activities In Vitro

1997 ◽  
Vol 78 (1) ◽  
pp. 539-544 ◽  
Author(s):  
Lisa R. Merlin ◽  
Robert K. S. Wong
Keyword(s):  
Guinea Pig ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Hippocampal Slices ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group I Mglurs ◽  
Synaptic Responses

Merlin, Lisa R. and Robert K. S. Wong. Role of group I metabotropic glutamate receptors in the patterning of epileptiform activities in vitro. J. Neurophysiol. 78: 539–544, 1997. In guinea pig hippocampal slices, picrotoxin elicited spontaneous epileptiform bursts 300–550 ms in duration. Additional application of ( R,S)-3,5-dihydroxyphenylglycine or ( S)-3-hydroxyphenylglycine, agonists specific for group I metabotropic glutamate receptors(mGluRs), or (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylicacid, a broad-spectrum mGluR agonist, converted picrotoxin-induced interictal bursts into prolonged discharges measured on the order of seconds. The prolonged discharges induced by selective group I mGluR agonist continued to be produced for hours after agonist removal. The antagonists ( S)-4-carboxyphenylglycine and (+)-α-methyl-4-carboxyphenylglycine had no effect on the duration of picrotoxin-induced interictal bursts. However, after agonist exposure, the persistent prolonged discharges occurring in the absence of agonist were reversibly suppressed by the antagonists, suggesting that the activity is maintained via endogenous activation of group I mGluRs by synaptically released glutamate. Our results suggest that, under some conditions, activation of group I mGluRs produces long-lasting enhancement of synaptic responses, mediated at least in part by autopotentiation of the group I mGluR response itself, which may result in the production of seizure discharges and contribute to epileptogenesis.

Effect of the Group II Metabotropic Glutamate Agonist, 2R,4R-APDC, Varies With Age, Layer, and Visual Experience in the Visual Cortex

1999 ◽  
Vol 82 (1) ◽  
pp. 86-93 ◽  
Author(s):  
C. J. Beaver ◽  
Q.-H. Ji ◽  
N. W. Daw
Keyword(s):  
Visual Cortex ◽  
Metabotropic Glutamate Receptors ◽  
Visual Stimulation ◽  
Ocular Dominance ◽  
Visual Response ◽  
Single Neurons ◽  
Metabotropic Glutamate ◽  
Layer 4 ◽  
Group Ii ◽  
Dark Rearing

Group II metabotropic glutamate receptors (mGluR 2/3) are distributed differentially across the layers of cat visual cortex, and this distribution varies with age. At 3–4 wk, mGluR 2/3 receptor immunoreactivity is present in all layers. By 6–8 wk of age, it is still present in extragranular layers (2, 3, 5, and 6) but has disappeared from layer 4, and dark-rearing postpones the disappearance of Group II receptors from layer 4. We examined the physiological effects of Group II activation, to see if these effects varied similarly. The responses of single neurons in cat primary visual cortex were recorded to visual stimulation, then the effect of iontophoresis of 2R,4R-4 aminopyrrolidine-2,4-decarboxylate (2R,4R-APDC), a Group II specific agonist, was observed in animals between 3 wk and adulthood. The effect of 2R,4R-APDC was generally suppressive, reducing both the visual response and spontaneous activity of single neurons. The developmental changes were in agreement with the immunohistochemical results: 2R,4R-APDC had effects on cells in all layers in animals of 3–4 wk but not in layer 4 of animals >6 wk old. Moreover, the effect of 2R,4R-APDC was reduced in the cortex of older animals (>22 wk). Dark-rearing animals to 47–54 days maintained the effects of 2R,4R-APDC in layer 4. The disappearance of Group II mGluRs from layer 4 between 3 and 6 wk of age is correlated with the segregation of ocular dominance columns in that layer, raising the possibility that mGluRs 2/3 are involved in this process.

Induction of NMDA Receptor-Dependent Long-Term Depression in Visual Cortex Does Not Require Metabotropic Glutamate Receptors

1999 ◽  
Vol 82 (6) ◽  
pp. 3594-3597 ◽  
Author(s):  
Nathaniel B. Sawtell ◽  
Kimberly M. Huber ◽  
John C. Roder ◽  
Mark F. Bear
Keyword(s):  
Visual Cortex ◽  
Nmda Receptor ◽  
Metabotropic Glutamate Receptors ◽  
Low Frequency ◽  
Long Term Depression ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Frequency Stimulation ◽  
Visual Cortical

We tested the role of group I mGluRs in the induction of long-term depression (LTD) in the visual cortex, using the novel mGluR antagonist LY341495 and mice lacking mGluR5, the predominant phosphoinositide (PI)-linked mGluR in the visual cortex. We find that LY341495 is a potent blocker of glutamate-stimulated PI hydrolysis in visual cortical synaptoneurosomes, and that it effectively antagonizes the actions of the mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (ACPD) on synaptic transmission in visual cortical slices. However, LY341495 has no effect on the induction of LTD by low-frequency stimulation. Furthermore, mice lacking mGluR5 show normal NMDA receptor-dependent LTD. These results indicate that group I mGluR activation is not required for the induction of NMDA receptor-dependent LTD in the visual cortex.

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