scholarly journals β-arrestin1 promotes tauopathy by transducing GPCR signaling, disrupting microtubules and autophagy

2021 ◽  
Vol 5 (3) ◽  
pp. e202101183
Author(s):  
Jung-AA Woo ◽  
Yan Yan ◽  
Teresa R Kee ◽  
Sara Cazzaro ◽  
Kyle C McGill Percy ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Cognitive Impairments ◽  
G Protein Coupled Receptors ◽  
Common Mechanism ◽  
Autophagy Flux ◽  
Metabotropic Glutamate ◽  
Downstream Signaling ◽  
Β2 Adrenergic Receptor ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) have been shown to play integral roles in Alzheimer’s disease pathogenesis. However, it is unclear how diverse GPCRs similarly affect Aβ and tau pathogenesis. GPCRs share a common mechanism of action via the β-arrestin scaffolding signaling complexes, which not only serve to desensitize GPCRs by internalization, but also mediate multiple downstream signaling events. As signaling via the GPCRs, β2-adrenergic receptor (β2AR), and metabotropic glutamate receptor 2 (mGluR2) promotes hyperphosphorylation of tau, we hypothesized that β-arrestin1 represents a point of convergence for such pathogenic activities. Here, we report that β-arrestins are not only essential for β2AR and mGluR2-mediated increase in pathogenic tau but also show that β-arrestin1 levels are increased in brains of Frontotemporal lobar degeneration (FTLD-tau) patients. Increased β-arrestin1 in turn drives the accumulation of pathogenic tau, whereas reduced ARRB1 alleviates tauopathy and rescues impaired synaptic plasticity and cognitive impairments in PS19 mice. Biochemical and cellular studies show that β-arrestin1 drives tauopathy by destabilizing microtubules and impeding p62/SQSTM1 autophagy flux by interfering with p62 body formation, which promotes pathogenic tau accumulation.

scholarly journals The G protein-Coupled Metabotropic Glutamate Receptor 1 controls neuronal macroautophagy

2020 ◽  
Author(s):  
Maribel Donoso ◽  
Luisa Speranza ◽  
Magdalena Kalinowska ◽  
Catherine Castillo ◽  
Claudia De Sanctis ◽  
...  
Keyword(s):  
G Protein ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Autophagy Flux ◽  
Metabotropic Glutamate ◽  
Evolutionarily Conserved ◽  
Metabotropic Glutamate Receptor 1 ◽  
Mglu1 Receptor ◽  
G Protein Coupled ◽  
The Brain

AbstractAutophagy is an evolutionarily conserved, highly regulated catabolic process critical to neuronal homeostasis, function and survival throughout organismal lifespan. However, the external factors and signals that control autophagy in neurons are still poorly understood. Here we report that the G protein-coupled metabotropic glutamate receptor 1 (mGlu1) contributes to control basal autophagy in the brain. Autophagy is upregulated in the brain of adult mGlu1 knockout mice and genetic deletion or pharmacological inhibition of native mGlu1 receptors enhances autophagy flux in neurons. The evolutionarily conserved adaptor protein FEZ1, identified by a genome-wide screen as mGlu1 receptor interacting partner, was found to participate in the regulation of neuronal autophagy and to be required for repression of autophagy flux by the mGlu1 receptor. Furthermore, FEZ1 appears to enable association of mGlu1 with Ulk1, a core component of the autophagy pathway. Thus, we propose that the mGlu1 receptor contributes to restrain constitutive autophagy in neurons.

scholarly journals Evaluation of FLIPR Calcium 3 Assay Kit—A New No-Wash Fluorescence Calcium Indicator Reagent

2003 ◽  
Vol 8 (5) ◽  
pp. 571-577 ◽  
Author(s):  
Yingxin Zhang ◽  
Dianne Kowal ◽  
Angela Kramer ◽  
John Dunlop
Keyword(s):  
Calcium Signaling ◽  
G Protein ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
G Protein Coupled Receptors ◽  
Metabotropic Glutamate Receptor 5 ◽  
Metabotropic Glutamate ◽  
Calcium Indicator ◽  
Indicator Dye ◽  
G Protein Coupled

We have evaluated the FLIPR Calcium 3 Assay Kit (Calcium 3), a new no-wash fluorescence calcium indicator dye reagent, for the measurement of agonist-stimulated calcium signaling in cells expressing the serotonin 2C (5-HT2C), metabotropic glutamate receptor 5 (mGluR5) and the vasopressin 2 (V2) G-protein-coupled receptors. Calcium 3 yielded equivalent (5-HT2C) or superior (mGluR5 and V2) sensitivity to FLUO-4 as indexed by the change in fluorescence counts following agonist application. Assay variability, indexed by CV, using Calcium 3 or FLUO-4 was equivalent with 5-HT2C receptor responses although CVs were reduced using Calcium 3 in the examples of the mGluR5 and V2 receptors. Receptor pharmacologies based on agonist EC50 values were identical when either Calcium 3 or FLUO-4 were utilized. Our results validate Calcium 3 as a compel-ling alternative to FLUO-4 in the choice of fluorescent dye reagent for studying G-protein-coupled receptors, providing the advantage of a homogenous, no-wash assay format. ( Journal of Biomolecular Screening 2003:571-577)

Abstract 3438: Gene Expression Profiling of G Protein-Coupled Receptors in the Adult Mouse Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Thomas Moore-Morris ◽  
Annie Varrault ◽  
Matteo E Mangoni ◽  
Anne Le Digarcher ◽  
Vincent Negre ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glutamate Receptor ◽  
Chemokine Receptor ◽  
Adult Mouse ◽  
Metabotropic Glutamate Receptor ◽  
G Protein Coupled Receptors ◽  
Mouse Heart ◽  
Rt Pcr ◽  
Metabotropic Glutamate ◽  
G Protein Coupled

The G protein-coupled receptors (GPCRs), one of the major targets of pharmaceutical drugs, are essential to many aspects of heart physiology including the regulation of heart rate, contractile force, cardiac remodelling and gene expression. The present study addresses the expression of endoGPCRs, all GPCRs excluding taste and odorant receptors, in each of the four cardiac chambers of adult mouse heart. High-throughput real-time RT-PCR was used to quantify 396 GPCRs and 7 associated proteins in right and left atria and ventricles. Statistical analysis of the most highly expressed transcripts showed that 47 were equally expressed throughout the heart and 89 were differentially expressed in at least one cardiac chamber. Among receptors uniformly expressed, we found well-characterized receptors such as the β2 adrenergic receptor, muscarinic M2 receptor, endothelin receptor type A (ETA) and purinoceptor P2Y2. Surprisingly enough, many of the most abundantly expressed GPCRs (e.g. belonging to the frizzled or chemokine receptor subfamilies) had not previously been identified in healthy heart. Repertoire analysis revealed genes specific to atria and ventricles. The atria exhibited the most specific signature with a lot of receptors not yet studied (receptors belonging to the EGF-like, Mucin-like, Decay-accelerating Factor and Mas-related subfamilies). No gene appeared to be significantly specific to the left or right side of the heart. RT-PCR data were confirmed at the protein level in all four cavities for several receptors and regulatory proteins including ETA, angiotensin receptor 1, protease-activated receptor 1, chemokine receptor CCR2, secreted frizzled related protein 1 and metabotropic glutamate receptor 1 (mGluR1). We also demonstrate that the mGluR1b splice variant is the sole highly expressed metabotropic glutamate receptor in adult mouse heart and is present and functional in isolated ventricular cardiomyocytes. Thus, large scale identification of the regional expression pattern of GPCRs in normal, and in the future in pathological conditions, might lead to the identification of new pharmacological targets for the treatment of human heart diseases.

Rab1 interacts directly with the β2-adrenergic receptor to regulate receptor anterograde trafficking

2012 ◽  
Vol 393 (6) ◽  
pp. 541-546 ◽  
Author(s):  
Maha M. Hammad ◽  
Yi-Qun Kuang ◽  
Alexa Morse ◽  
Denis J. Dupré
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Direct Interaction ◽  
Potential Interaction ◽  
G Protein Coupled Receptors ◽  
Endocytic Pathway ◽  
Β2 Adrenergic Receptor ◽  
G Protein Coupled

Abstract Very little is understood about the trafficking of G protein-coupled receptors (GPCRs) from the endoplasmic reticulum (ER) to the plasma membrane. Rab guanosine triphosphatases (GTPases) are known to participate in the trafficking of various GPCRs via a direct interaction during the endocytic pathway, but whether this occurs in the anterograde pathway is unknown. We evaluated the potential interaction of Rab1, a GTPase known to regulate β2-adrenergic receptor (β2AR) trafficking, and its effect on export from the ER. Our results show that GTP-bound Rab1 interacts with the F(x)6LL motif of β2AR. Receptors lacking the interaction motif fail to traffic properly, suggesting that a direct interaction with Rab1 is required for β2AR anterograde trafficking.

scholarly journals β2-adrenergic receptor regulates ER-mitochondria contacts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Youngshin Lim ◽  
Il-Taeg Cho ◽  
Helmut G. Rennke ◽  
Ginam Cho
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
G Protein Coupled Receptors ◽  
Cellular Functions ◽  
Cellular Environment ◽  
Downstream Effectors ◽  
Β2 Adrenergic Receptor ◽  
Physiological Demands ◽  
G Protein Coupled

AbstractInteractions between the endoplasmic reticulum (ER) and mitochondria (Mito) are crucial for many cellular functions, and their interaction levels change dynamically depending on the cellular environment. Little is known about how the interactions between these organelles are regulated within the cell. Here we screened a compound library to identify chemical modulators for ER-Mito contacts in HEK293T cells. Multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (β-ARs) in particular, scored in this screen. Analyses in multiple orthogonal assays validated that β2-AR activation promotes physical and functional interactions between the two organelles. Furthermore, we have elucidated potential downstream effectors mediating β2-AR-induced ER-Mito contacts. Together our study identifies β2-AR signaling as an important regulatory pathway for ER-Mito coupling and highlights the role of these contacts in responding to physiological demands or stresses.

Structure and Regulation of G Protein-Coupled Receptors: The β2-Adrenergic Receptor as a Model

1991 ◽  
pp. 1-39 ◽  
Author(s):  
Sheila Collins ◽  
Martin J. Lohse ◽  
Brian O'Dowd ◽  
Marc G. Caron ◽  
Robert J. Lefkowitz
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
G Protein Coupled Receptors ◽  
Β2 Adrenergic Receptor ◽  
G Protein Coupled
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