A Critical Role for Sorting Nexin 1 in the Trafficking of Metabotropic Glutamate Receptors

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.

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Metabotropic Glutamate Receptors 1 Regulates Rat Carotid Body Response to Acute Hypoxia via Presynaptic Mechanism

Frontiers in Neuroscience ◽

10.3389/fnins.2021.741214 ◽

2021 ◽

Vol 15 ◽

Author(s):

Chaohong Li ◽

Baosheng Zhao ◽

Chenlu Zhao ◽

Lu Huang ◽

Yuzhen Liu

Keyword(s):

Glutamate Receptors ◽

Carotid Body ◽

Cellular Localization ◽

Metabotropic Glutamate Receptors ◽

Physiological Function ◽

Acute Hypoxia ◽

Critical Role ◽

Type I ◽

Metabotropic Glutamate ◽

Group I

Background: The carotid body (CB) plays a critical role in oxygen sensing; however, the role of glutamatergic signaling in the CB response to hypoxia remains uncertain. We previously found that functional multiple glutamate transporters and inotropic glutamate receptors (iGluRs) are expressed in the CB. The aim of this present research is to investigate the expression of group I metabotropic glutamate receptors (mGluRs) (mGluR1 and 5) in the CB and its physiological function in rat CB response to acute hypoxia.Methods: RT-PCR and immunostaining were conducted to examine the mRNA and protein expression of group I mGluRs in the human and rat CB. Immunofluorescence staining was performed to examine the cellular localization of mGluR1 in the rat CB. In vitro carotid sinus nerve (CSN) discharge recording was performed to detect the physiological function of mGluR1 in CB response to acute hypoxia.Results: We found that (1) mRNAs of mGluR1 and 5 were both expressed in the human and rat CB. (2) mGluR1 protein rather than mGluR5 protein was present in rat CB. (3) mGluR1 was distributed in type I cells of rat CB. (4) Activation of mGluR1 inhibited the hypoxia-induced enhancement of CSN activity (CSNA), as well as prolonged the latency time of CB response to hypoxia. (5) The inhibitory effect of mGluR1 activation on rat CB response to hypoxia could be blocked by GABAB receptor antagonist.Conclusion: Our findings reveal that mGluR1 in CB plays a presynaptic feedback inhibition on rat CB response to hypoxia.

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The metabotropic glutamate receptors: their second intracellular loop plays a critical role in the G-protein coupling specificity

Biochemical Society Transactions ◽

10.1042/bst0230091 ◽

1995 ◽

Vol 23 (1) ◽

pp. 91-96 ◽

Cited By ~ 19

Author(s):

J.-P. Pin ◽

J. Gomeza ◽

C. Joly ◽

J. Bockaert

Keyword(s):

Glutamate Receptors ◽

G Protein ◽

Metabotropic Glutamate Receptors ◽

Critical Role ◽

Intracellular Loop ◽

G Protein Coupling ◽

Protein Coupling ◽

Metabotropic Glutamate ◽

Coupling Specificity

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Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors

10.1101/2021.02.04.429701 ◽

2021 ◽

Author(s):

Jordana K. Thibado ◽

Jean-Yves Tano ◽

Joon Lee ◽

Leslie Salas-Estrada ◽

Davide Provasi ◽

...

Keyword(s):

Glutamate Receptors ◽

Single Molecule ◽

Metabotropic Glutamate Receptors ◽

Transmembrane Domain ◽

Critical Role ◽

Transmembrane Helix ◽

Variable Region ◽

Metabotropic Glutamate ◽

Initial Activation ◽

G Protein Coupled

AbstractThe metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G protein-coupled receptors that contain both a seven-helix transmembrane domain (TMD) and a large extracellular ligand-binding domain (LBD) which enables stable dimerization. While numerous studies have revealed variability across subtypes in the initial activation steps at the level of LBD dimers, an understanding of inter-TMD interaction and rearrangement remains limited. Here we use a combination of single molecule fluorescence, molecular dynamics, functional assays, and conformational sensors to reveal that distinct TMD assembly properties drive differences between mGluR subtypes. We uncover a variable region within transmembrane helix 4 (TM4) that contributes to homo- and heterodimerization in a subtype-specific manner and tunes orthosteric, allosteric and basal activation. We also confirm a critical role for a conserved inter-TM6 interface in stabilizing the active state during orthosteric or allosteric activation. Together this study informs a working model of inter-TMD rearrangement that drives mGluR function.

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

Cell Death Discovery ◽

10.1038/s41420-020-00389-6 ◽

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.

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Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease

Frontiers in Neural Circuits ◽

10.3389/fncir.2021.634875 ◽

2021 ◽

Vol 15 ◽

Author(s):

Hayato Matsunaga ◽

Jun Aruga

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Synapse Formation ◽

Critical Role ◽

Photoreceptor Cells ◽

Excitatory Input ◽

Bipolar Cells ◽

Rod Photoreceptor ◽

Post Traumatic Stress ◽

Metabotropic Glutamate

Trans-regulation of G protein-coupled receptors (GPCRs) by leucine-rich repeat (LRR) transmembrane proteins has emerged as a novel type of synaptic molecular interaction in the last decade. Several studies on LRR–GPCR interactions have revealed their critical role in synapse formation and in establishing synaptic properties. Among them, LRR–GPCR interactions between extracellular LRR fibronectin domain-containing family proteins (Elfn1 and Elfn2) and metabotropic glutamate receptors (mGluRs) are particularly interesting as they can affect a broad range of synapses through the modulation of signaling by glutamate, the principal excitatory transmitter in the mammalian central nervous system (CNS). Elfn–mGluR interactions have been investigated in hippocampal, cortical, and retinal synapses. Postsynaptic Elfn1 in the hippocampus and cerebral cortex mediates the tonic regulation of excitatory input onto somatostatin-positive interneurons (INs) through recruitment of presynaptic mGluR7. In the retina, presynaptic Elfn1 binds to mGluR6 and is necessary for synapse formation between rod photoreceptor cells and rod-bipolar cells. The repertoire of binding partners for Elfn1 and Elfn2 includes all group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8), and both Elfn1 and Elfn2 can alter mGluR-mediated signaling through trans-interaction. Importantly, both preclinical and clinical studies have provided support for the involvement of the Elfn1–mGluR7 interaction in attention-deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and epilepsy. In fact, Elfn1–mGluR7-associated disorders may reflect the altered function of somatostatin-positive interneuron inhibitory neural circuits, the mesolimbic and nigrostriatal dopaminergic pathway, and habenular circuits, highlighting the need for further investigation into this interaction.

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Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors

eLife ◽

10.7554/elife.67027 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jordana K Thibado ◽

Jean-Yves Tano ◽

Joon Lee ◽

Leslie Salas-Estrada ◽

Davide Provasi ◽

...

Keyword(s):

Glutamate Receptors ◽

Single Molecule ◽

Metabotropic Glutamate Receptors ◽

Transmembrane Domain ◽

Critical Role ◽

Transmembrane Helix ◽

Variable Region ◽

Metabotropic Glutamate ◽

Initial Activation ◽

G Protein Coupled

The metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G protein-coupled receptors that contain both a seven-helix transmembrane domain (TMD) and a large extracellular ligand-binding domain (LBD) which enables stable dimerization. While numerous studies have revealed variability across subtypes in the initial activation steps at the level of LBD dimers, an understanding of inter-TMD interaction and rearrangement remains limited. Here we use a combination of single molecule fluorescence, molecular dynamics, functional assays, and conformational sensors to reveal that distinct TMD assembly properties drive differences between mGluR subtypes. We uncover a variable region within transmembrane helix 4 (TM4) that contributes to homo- and heterodimerization in a subtype-specific manner and tunes orthosteric, allosteric and basal activation. We also confirm a critical role for a conserved inter-TM6 interface in stabilizing the active state during orthosteric or allosteric activation. Together this study shows that inter-TMD assembly and dynamic rearrangement drive mGluR function with distinct properties between subtypes.

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