Interclass GPCR heteromerization affects localization and trafficking

Membrane trafficking processes regulate G protein–coupled receptor (GPCR) activity. Although class A GPCRs are capable of activating G proteins in a monomeric form, they can also potentially assemble into functional GPCR heteromers. Here, we showed that the class A serotonin 5-HT2A receptors (5-HT2ARs) affected the localization and trafficking of class C metabotropic glutamate receptor 2 (mGluR2) through a mechanism that required their assembly as heteromers in mammalian cells. In the absence of agonists, 5-HT2AR was primarily localized within intracellular compartments, and coexpression of 5-HT2AR with mGluR2 increased the intracellular distribution of the otherwise plasma membrane–localized mGluR2. Agonists for either 5-HT2AR or mGluR2 differentially affected trafficking through Rab5-positive endosomes in cells expressing each component of the 5-HT2AR–mGluR2 heterocomplex alone, or together. In addition, overnight pharmacological 5-HT2AR blockade with clozapine, but not with M100907, decreased mGluR2 density through a mechanism that involved heteromerization between 5-HT2AR and mGluR2. Using TAT-tagged peptides and chimeric constructs that are unable to form the interclass 5-HT2AR–mGluR2 complex, we demonstrated that heteromerization was necessary for the 5-HT2AR–dependent effects on mGluR2 subcellular distribution. The expression of 5-HT2AR also augmented intracellular localization of mGluR2 in mouse frontal cortex pyramidal neurons. Together, our data suggest that GPCR heteromerization may itself represent a mechanism of receptor trafficking and sorting.

Download Full-text

Metabotropic Glutamate Receptor Trafficking and its Role in Drug-Induced Neurobehavioral Plasticity

Brain Plasticity ◽

10.3233/bpl-210120 ◽

2021 ◽

pp. 1-16

Author(s):

Peter U. Hámor ◽

Marek Schwendt

Keyword(s):

Glutamate Receptor ◽

Membrane Trafficking ◽

Metabotropic Glutamate Receptor ◽

Neuropsychiatric Disorders ◽

Surface Expression ◽

Receptor Trafficking ◽

Fine Tuning ◽

Cell Surface Expression ◽

Metabotropic Glutamate ◽

Glutamate Receptor Trafficking

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system that guides developmental and experience-dependent changes in many cellular substrates and brain circuits, through the process collectively referred to as neurobehavioral plasticity. Regulation of cell surface expression and membrane trafficking of glutamate receptors represents an important mechanism that assures optimal excitatory transmission, and at the same time, also allows for fine-tuning neuronal responses to glutamate. On the other hand, there is growing evidence implicating dysregulated glutamate receptor trafficking in the pathophysiology of several neuropsychiatric disorders. This review provides up-to-date information on the molecular determinants regulating trafficking and surface expression of metabotropic glutamate (mGlu) receptors in the rodent and human brain and discusses the role of mGluR trafficking in maladaptive synaptic plasticity produced by addictive drugs. As substantial evidence links glutamatergic dysfunction to the progression and the severity of drug addiction, advances in our understanding of mGluR trafficking may provide opportunities for the development of novel pharmacotherapies of addiction and other neuropsychiatric disorders.

Download Full-text

Faculty Opinions recommendation of Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu5) X-ray Structures.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732704940.793543297 ◽

2018 ◽

Author(s):

Dario Doller

Keyword(s):

G Protein ◽

Glutamate Receptor ◽

Metabotropic Glutamate Receptor ◽

Allosteric Modulators ◽

G Protein Coupled Receptor ◽

Metabotropic Glutamate Receptor 5 ◽

X Ray ◽

Metabotropic Glutamate ◽

G Protein Coupled

Download Full-text

Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

Molecular Brain ◽

10.1186/s13041-021-00795-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Jesús David Urbano-Gámez ◽

Juan José Casañas ◽

Itziar Benito ◽

María Luz Montesinos

Keyword(s):

Intellectual Disability ◽

Pyramidal Neurons ◽

Metabotropic Glutamate Receptor ◽

Therapeutic Potential ◽

Mammalian Target Of Rapamycin ◽

Memory Deficits ◽

Prenatal Treatment ◽

Hippocampal Pyramidal Neurons ◽

Metabotropic Glutamate ◽

Mushroom Spines

AbstractDown syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we characterize the proteome of hippocampal synaptoneurosomes (SNs) from these mice, and found a predicted alteration of synaptic plasticity pathways, including long term depression (LTD). Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-LTD) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin has a positive pharmacological effect on both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.

Download Full-text

Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

International Journal of Molecular Sciences ◽

10.3390/ijms22063241 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3241

Author(s):

Raudah Lazim ◽

Donghyuk Suh ◽

Jai Woo Lee ◽

Thi Ngoc Lan Vu ◽

Sanghee Yoon ◽

...

Keyword(s):

G Protein ◽

Protein Interactions ◽

Metabotropic Glutamate Receptor ◽

Three Dimensional ◽

Allosteric Modulation ◽

Experimental Investigations ◽

G Protein Coupled Receptor ◽

Metabotropic Glutamate ◽

Gpcr Activation ◽

G Protein Coupled

G protein-coupled receptor (GPCR) oligomerization, while contentious, continues to attract the attention of researchers. Numerous experimental investigations have validated the presence of GPCR dimers, and the relevance of dimerization in the effectuation of physiological functions intensifies the attractiveness of this concept as a potential therapeutic target. GPCRs, as a single entity, have been the main source of scrutiny for drug design objectives for multiple diseases such as cancer, inflammation, cardiac, and respiratory diseases. The existence of dimers broadens the research scope of GPCR functions, revealing new signaling pathways that can be targeted for disease pathogenesis that have not previously been reported when GPCRs were only viewed in their monomeric form. This review will highlight several aspects of GPCR dimerization, which include a summary of the structural elucidation of the allosteric modulation of class C GPCR activation offered through recent solutions to the three-dimensional, full-length structures of metabotropic glutamate receptor and γ-aminobutyric acid B receptor as well as the role of dimerization in the modification of GPCR function and allostery. With the growing influence of computational methods in the study of GPCRs, we will also be reviewing recent computational tools that have been utilized to map protein–protein interactions (PPI).

Download Full-text

Metabotropic glutamate receptor-mediated suppression of L-type calcium current in acutely isolated neocortical neurons

Journal of Neurophysiology ◽

10.1152/jn.1992.68.3.833 ◽

1992 ◽

Vol 68 (3) ◽

pp. 833-842 ◽

Cited By ~ 71

Author(s):

R. J. Sayer ◽

P. C. Schwindt ◽

W. E. Crill

Keyword(s):

Glutamate Receptor ◽

Pyramidal Neurons ◽

Metabotropic Glutamate Receptor ◽

High Threshold ◽

External Application ◽

Metabotropic Glutamate ◽

Neocortical Neurons ◽

Old Rats ◽

Low Threshold ◽

Ca2 Channels

1. The effects of metabotropic glutamate receptor (mGluR) stimulation on whole-cell Ca2+ currents were studied in pyramidal neurons isolated from the dorsal frontoparietal neocortex of rat. The selective mGluR agonist cis-(+/-)-1-aminocyclopentane-1,3-dicarboxylic acid [trans-ACPD (100 microM)] suppressed the peak high-threshold Ca2+ current by 21 +/- 1.7% (mean +/- SE) in 40 of 43 cells from 10- to 21-day-old rats. Consistent with previous findings for mGluR, glutamate, quisqualate, and ibotenate [but not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)] reduced the Ca2+ currents, and the responses were not blocked by the ionotropic glutamate receptor antagonists 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonovaleric acid (APV). EC50S for Ca2+ current suppression were 29 nM for quisqualate, 2.3 microM for glutamate, and 13 microM for trans-ACPD. 2. The low-threshold Ca2+ current was not modulated by trans-ACPD. The component of the high-threshold CA2+ current suppressed by mGluR was determined by pharmacology; the responses were not affected by omega-conotoxin GVIA but were occluded by the dihydropyridine Ca2+ antagonist nifedipine. Ca2+ tail currents prolonged by the dihydropyridine Ca2+ agonist (+)-SDZ 202-79] were suppressed by mGluR stimulation in parallel with the peak current. These findings strongly suggest that L-type Ca2+ channels are modulated by mGluR. 3. In neurons dialyzed with 100 microM guanosine 5'-(gamma-thio)triphosphate (GTP-gamma-S), Ca2+ current suppression was elicited by the first application of trans-ACPD (in 5 of 6 cells), but not by subsequent applications. Responses in neurons dialyzed with 2 mM guanosine 5'-(beta-thio)diphosphate (GDP-beta-S) were significantly smaller than controls. The results are consistent with mGluR acting via linkage to a G protein. 4. The responses to mGluR agonists were smaller when the external Ca2+ was replaced by Ba2+, indicating that some part of the mechanism underlying the current suppression is Ca2+ dependent. Because mGluR stimulates phosphoinositide turnover and release of Ca2+ from intracellular stores in other types of neurons, the possibility of released Ca2+ mediating inactivation of Ca2+ channels was considered. However, the Ca2+ current suppression was not attenuated by strong intracellular Ca2+ buffering [20 mM bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA)], by dialysis with 100 microM inositol-1,4,5-triphosphate (IP3), or by external application of 1 microM thapsigargin. 5. We conclude that in neocortical neurons, one action of mGluR is to suppress the component of high-threshold Ca2+ current conducted by L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)

Download Full-text

Altered Short-Term Synaptic Plasticity in Mice Lacking the Metabotropic Glutamate Receptor mGlu7

The Scientific World JOURNAL ◽

10.1100/tsw.2002.146 ◽

2002 ◽

Vol 2 ◽

pp. 730-737 ◽

Cited By ~ 35

Author(s):

Trevor J. Bushell ◽

Gilles Sansig ◽

Valerie J. Collett ◽

Herman van der Putten ◽

Graham L. Collingridge

Keyword(s):

Synaptic Plasticity ◽

Molecular Mechanisms ◽

Pyramidal Neurons ◽

Metabotropic Glutamate Receptor ◽

Long Term Potentiation ◽

Short Term ◽

Metabotropic Glutamate ◽

Term Potentiation ◽

Commissural Pathway ◽

Frequency Facilitation

Eight subtypes of metabotropic glutamate (mGlu) receptors have been identified of which two, mGlu5 and mGlu7, are highly expressed at synapses made between CA3 and CA1 pyramidal neurons in the hippocampus. This input, the Schaffer collateral-commissural pathway, displays robust long-term potentiation (LTP), a process believed to utilise molecular mechanisms that are key processes involved in the synaptic basis of learning and memory. To investigate the possible function in LTP of mGlu7 receptors, a subtype for which no specific antagonists exist, we generated a mouse lacking this receptor, by homologous recombination. We found that LTP could be induced in mGlu7-/- mice and that once the potentiation had reached a stable level there was no difference in the magnitude of LTP between mGlu7-/- mice and their littermate controls. However, the initial decremental phase of LTP, known as short-term potentiation (STP), was greatly attenuated in the mGlu7-/- mouse. In addition, there was less frequency facilitation during, and less post-tetanic potentiation following, a high frequency train in the mGlu7-/- mouse. These results show that the absence of mGlu7 receptors results in alterations in short-term synaptic plasticity in the hippocampus.

Download Full-text