Signaling Mechanisms Underlying Group I mGluR-Induced Persistent AHP Suppression in CA3 Hippocampal Neurons

2008 ◽  
Vol 99 (3) ◽  
pp. 1105-1118 ◽  
Author(s):  
Steven R. Young ◽  
Riccardo Bianchi ◽  
Robert K. S. Wong
Keyword(s):  
Protein Synthesis ◽  
Map Kinase ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
P38 Map Kinase ◽  
Temperature Dependent ◽  
Kinase Activation ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Mglur5 Antagonist

Activation of group I metabotropic glutamate receptors (mGluRs) leads to a concerted modulation of spike afterpotentials in guinea pig hippocampal neurons including a suppression of both medium and slow afterhyperpolarizations (AHPs). Suppression of AHPs may be long-lasting, in that it persists after washout of the agonist. Here, we show that persistent AHP suppression differs from short-term, transient suppression in that distinct and additional signaling processes are required to render the suppression persistent. Persistent AHP suppression followed DHPG application for 30 min, but not DHPG application for 5 min. Persistent AHP suppression was temperature dependent, occurring at 30–31°C, but not at 25–26°C. Preincubation of slices in inhibitors of protein synthesis (cycloheximide or anisomycin) prevented the persistent suppression of AHPs by DHPG. Similarly, preincubation of slices in an inhibitor of p38 MAP kinase (SB 203580) prevented persistent AHP suppression. In contrast, a blocker of p42/44 MAP kinase activation (PD 98059) had no effect on persistent AHP suppression. Additionally, we show that the mGluR5 antagonist MPEP, but not the mGluR1 antagonist LY 367385, prevented DHPG-induced persistent AHP suppression. Thus persistent AHP suppression by DHPG in hippocampal neurons requires activation of mGluR5. In addition, activation of p38 MAP kinase signaling and protein synthesis are required to impart persistence to the DHPG-activated AHP suppression.

scholarly journals Temporal Quantitative Proteomics of mGluR-induced Protein Translation and Phosphorylation in Neurons

2020 ◽  
Vol 19 (12) ◽  
pp. 1952-1967
Author(s):  
Charlotte A. G. H. van Gelder ◽  
Renske Penning ◽  
Tim S. Veth ◽  
Lisa A. E. Catsburg ◽  
Casper C. Hoogenraad ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Kinase Inhibitors ◽  
Protein Translation ◽  
Autism Spectrum ◽  
Metabotropic Glutamate ◽  
Neuronal Synapses ◽  
Group I

At neuronal synapses, activation of group I metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein synthesis and the internalization of AMPA-type glutamate receptors. Dysregulation of these processes has been implicated in the development of mental disorders such as autism spectrum disorders and therefore merit a better understanding on a molecular level. Here, to study mGluR-induced signaling pathways, we integrated quantitative phosphoproteomics with the analyses of newly synthesized proteins via bio-orthogonal amino acids (azidohomoalanine) in a pulsed labeling strategy in cultured hippocampal neurons stimulated with DHPG, a specific agonist for group I mGluRs. We identified several kinases with important roles in DHPG-induced mGluR activation, which we confirmed using small molecule kinase inhibitors. Furthermore, changes in the AMPA receptor endocytosis pathway in both protein synthesis and protein phosphorylation were identified, whereby Intersectin-1 was validated as a novel player in this pathway. This study revealed several new insights into the molecular pathways downstream of group I mGluR activation in hippocampal neurons, and provides a rich resource for further analyses.

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.

scholarly journals Cyclic ADP Ribose-Dependent Ca2+ Release by Group I Metabotropic Glutamate Receptors in Acutely Dissociated Rat Hippocampal Neurons

PLoS ONE ◽  
2011 ◽  
Vol 6 (10) ◽  
pp. e26625 ◽  
Author(s):  
Jong-Woo Sohn ◽  
Weon-Jin Yu ◽  
Doyun Lee ◽  
Hee-Sup Shin ◽  
Suk-Ho Lee ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Cyclic Adp Ribose

scholarly journals Temporal quantitative proteomics of protein translation and phosphorylation in synaptic plasticity

2019 ◽  
Author(s):  
Charlotte AGH van Gelder ◽  
Renske Penning ◽  
Lisa Catsburg ◽  
Casper C Hoogenraad ◽  
Harold D MacGillavry ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Protein Translation ◽  
Autism Spectrum ◽  
Metabotropic Glutamate ◽  
Neuronal Synapses

AbstractAt neuronal synapses, activation of metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein synthesis and the internalization of AMPA-type glutamate receptors. Dysregulation of these processes has been implicated in the development of mental disorders such as autism spectrum disorders and therefore merit a better understanding on a molecular level. Here, to study mGluR-LTD, we integrated quantitative high-resolution phosphoproteomics with the analyses of newly synthesized proteins via bio-orthogonal amino acids (azidohomoalanine) in a pulsed labeling strategy combined with tandem mass tag label-based quantification in cultured hippocampal neurons stimulated with DHPG. We identified several kinases with important roles in DHPG-mGluR-LTD, which we confirmed using small molecule kinase inhibitors. Furthermore, changes in the AMPA receptor endocytosis pathway in both protein synthesis and protein phosphorylation upon LTD were identified, whereby Intersectin-1 was validated as a vital player in this pathway. This study revealed several novel insights into the molecular mechanisms underlying mGluR-LTD and provides a broad view on its molecular basis, which serves as a rich resource for further analyses.

Differential Roles for mGluR1 and mGluR5 in the Persistent Prolongation of Epileptiform Bursts

2002 ◽  
Vol 87 (1) ◽  
pp. 621-625 ◽  
Author(s):  
Lisa R. Merlin
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Hippocampal Slices ◽  
Receptor Subtypes ◽  
Metabotropic Glutamate ◽  
Selective Agonist ◽  
Transient Activation ◽  
Group I ◽  
Induction Process ◽  
Mglur5 Antagonist ◽  
Subtype Selective

Transient activation of group I metabotropic glutamate receptors (mGluRs) with the selective agonist ( S)-3,5-dihydroxyphenylglycine (DHPG) produces persistent prolongation of epileptiform bursts in guinea pig hippocampal slices, the maintenance of which can be reversibly suppressed with group I mGluR antagonists. To determine the relative roles of mGluR1 and mGluR5 in these group I mGluR-dependent induction and maintenance processes, subtype-selective antagonists were utilized. In the presence of picrotoxin, DHPG (50 μM, 20–45 min) converted interictal bursts into 1- to 3-s discharges that persisted for hours following washout of the mGluR agonist. 2-methyl-6-(phenylethynyl)-pyridine (MPEP, an mGluR5 antagonist; 25 μM) and (+)-2-methyl-4-carboxyphenylglycine (LY367385, an mGluR1 antagonist; 20–25 μM) each significantly suppressed the ongoing expression of the mGluR-induced prolonged bursts. However, LY367385 was more effective, reducing the burst prolongation by nearly 90%; MPEP only produced a 64% reduction in burst prolongation. Nevertheless, MPEP was more effective at preventing the induction of the burst prolongation; all 10 slices tested failed to express prolonged bursts both during and after co-application of DHPG with MPEP. Co-application of DHPG with LY367385, in contrast, resulted in significant burst prolongation (in 68% of slices tested) that was revealed on washout of the two agents. These results suggest that while both receptor subtypes participate in both the induction and maintenance of mGluR-mediated burst prolongation, mGluR1 activation plays a greater role in sustaining the expression of prolonged bursts, whereas mGluR5 activation may be a more critical contributor to the induction process underlying this type of epileptogenesis.

Group I Metabotropic Glutamate Receptors Are Differentially Expressed by Two Populations of Olfactory Bulb Granule Cells

2007 ◽  
Vol 97 (4) ◽  
pp. 3136-3141 ◽  
Author(s):  
Thomas Heinbockel ◽  
Kathryn A. Hamilton ◽  
Matthew Ennis
Keyword(s):  
Olfactory Bulb ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Granule Cells ◽  
Mitral Cell ◽  
Mitral Cells ◽  
Patch Clamp Recording ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Bath Application

In the main olfactory bulb, several populations of granule cells (GCs) can be distinguished based on the soma location either superficially, interspersed with mitral cells within the mitral cell layer (MCL), or deeper, within the GC layer (GCL). Little is known about the physiological properties of superficial GCs (sGCs) versus deep GCs (dGCs). Here, we used patch-clamp recording methods to explore the role of Group I metabotropic glutamate receptors (mGluRs) in regulating the activity of GCs in slices from wildtype and mGluR−/− mutant mice. In wildtype mice, bath application of the selective Group I mGluR agonist DHPG depolarized and increased the firing rate of both GC subtypes. In the presence of blockers of fast synaptic transmission (APV, CNQX, gabazine), DHPG directly depolarized both GC subtypes, although the two GC subtypes responded differentially to DHPG in mGluR1−/− and mGluR5−/− mice. DHPG depolarized sGCs in slices from mGluR5−/− mice, although it had no effect on sGCs in slices from mGluR1−/− mice. By contrast, DHPG depolarized dGCs in slices from mGluR1−/− mice but had no effect on dGCs in slices from mGluR5−/− mice. Previous studies showed that mitral cells express mGluR1 but not mGluR5. The present results therefore suggest that sGCs are more similar to mitral cells than dGCs in terms of mGluR expression.

Sign in / Sign up

Export Citation Format

Share Document