Agonist-dependent Signaling by Group I Metabotropic Glutamate Receptors Is Regulated by Association with Lipid Domains

Kumari, Rita; Castillo, Catherine; Francesconi, Anna

doi:10.1074/jbc.m113.475863

Cited by 39 publications

(48 citation statements)

References 80 publications

(108 reference statements)

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“…At any rate, our data are consistent with a study which showed that ATP-induced Ca 2+ increases originated in specific areas of the caveolin-enriched plasma membrane in endothelial cells, suggesting that caveolin may be involved in the initiation of agonist-stimulated Ca 2+ signaling [44]. However, another report suggests that the interaction of mGlu1 receptor and caveolin-1 is not required for its localization to lipid rafts [40]. It showed that mGlu1 receptor mutated with two caveolin-1 binding sites displayed comparable agonist binding affinity and agonist-induced localization to lipid rafts with wild-type.…”

Section: Discussionsupporting

confidence: 91%

“…It is also possible that differences of agonist binding affinity according to differential lipid raft localization might regulate the coupling of the receptor signaling. Another recent study suggests that mGlu1α is recruited by agonist to lipid rafts and this is supported in part by intact cholesterol recognition/interaction amino acid consensus (CRAC) motif [40]. The data are in line with our result which showed impairment of Ca 2+ signaling by cholesterol extracting drug, mβCD, implying the importance of cholesterol in the receptor function.…”

Section: Discussionsupporting

confidence: 90%

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Lipid rafts serve as signaling platforms for mGlu1 receptor-mediated calcium signaling in association with caveolin

et al. 2014

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BackgroundGroup I metabotropic glutamate receptors (mGlu1/5 receptors) have important roles in synaptic activity in the central nervous system. They modulate neuronal excitability by mobilizing intracellular Ca2+ following receptor activation. Also, accumulating evidence has indicated the association of Ca2+ signaling with lipid rafts. Caveolin, an adaptor protein found in a specialized subset of lipid rafts, has been reported to promote the localization of membrane proteins to lipid rafts.ResultsIn the present study, we investigated the role of lipid rafts on the mGlu1α receptor-mediated Ca2+ signaling in association with caveolin in hippocampal primary neurons and HEK293 cells. We show that the disruption of lipid rafts using methyl-β-cyclodextrin markedly decreased mGlu1α receptor-mediated Ca2+ transients and lipid rafts localization of the receptor. Furthermore, transfection of mGlu1α receptor with mutated caveolin-binding domain reduced localization of the receptor to lipid rafts. Also, application of a peptide blocker of mGlu1α receptor and caveolin binding reduced the Ca2+ signaling and the lipid rafts localization.ConclusionsTaken together, these results suggest that the binding of mGlu1α receptor to caveolin is crucial for its lipid rafts localization and mGlu1α receptor-mediated Ca2+ transients.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Lipid rafts serve as signaling platforms for mGlu1 receptor-mediated calcium signaling in association with caveolin

et al. 2014

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“…Lipids are integral to the structure of the Kv1.2 potassium channel (Long et al, 2007). Metabotropic glutamate receptors are modulated by cholesterol (Kumari et al, 2013), and many ion channels are affected by phosphatidylinositol 4,5-biphosphate (PIP 2 ; Poveda et al, 2014). Phosphatidylinositol 3,4,5triphosphate (PIP 3 ) is localized to membrane rafts (Hansen, 2015) and maintains -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor clustering (Arendt et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

The actions of volatile anesthetics: a new perspective

Weinrich

Worcester

2018

Acta Crystallogr D Struct Biol

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“…Flotillin-1 is abundantly expressed in the brain and its selective association with raft membranes has been extensively characterized in both primary neurons and brain tissue [ 56 ] and thus represents a reliable marker of lipid raft enrichment. In contrast, TfR1 is excluded from lipid raft membranes under resting or stimulated conditions [ 57 ] in both primary cells and native tissue and thus affords a reliable indicator of non-raft membranes. We found Flotillin-1 to be consistently enriched in three buoyant gradient fractions (fractions 3 to 5; Fig 1A ) in both mutant and wild type mouse brain whereas TfR1 appeared concentrated in heavy gradient fractions and virtually absent from buoyant, lipid raft enriched membranes ( Fig 1B ).…”

Section: Resultsmentioning

confidence: 99%

Quantitative Profiling of Brain Lipid Raft Proteome in a Mouse Model of Fragile X Syndrome

2015

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Fragile X Syndrome, a leading cause of inherited intellectual disability and autism, arises from transcriptional silencing of the FMR1 gene encoding an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). FMRP can regulate the expression of approximately 4% of brain transcripts through its role in regulation of mRNA transport, stability and translation, thus providing a molecular rationale for its potential pleiotropic effects on neuronal and brain circuitry function. Several intracellular signaling pathways are dysregulated in the absence of FMRP suggesting that cellular deficits may be broad and could result in homeostatic changes. Lipid rafts are specialized regions of the plasma membrane, enriched in cholesterol and glycosphingolipids, involved in regulation of intracellular signaling. Among transcripts targeted by FMRP, a subset encodes proteins involved in lipid biosynthesis and homeostasis, dysregulation of which could affect the integrity and function of lipid rafts. Using a quantitative mass spectrometry-based approach we analyzed the lipid raft proteome of Fmr1 knockout mice, an animal model of Fragile X syndrome, and identified candidate proteins that are differentially represented in Fmr1 knockout mice lipid rafts. Furthermore, network analysis of these candidate proteins reveals connectivity between them and predicts functional connectivity with genes encoding components of myelin sheath, axonal processes and growth cones. Our findings provide insight to aid identification of molecular and cellular dysfunctions arising from Fmr1 silencing and for uncovering shared pathologies between Fragile X syndrome and other autism spectrum disorders.

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Agonist-dependent Signaling by Group I Metabotropic Glutamate Receptors Is Regulated by Association with Lipid Domains

Cited by 39 publications

References 80 publications

Lipid rafts serve as signaling platforms for mGlu1 receptor-mediated calcium signaling in association with caveolin

Lipid rafts serve as signaling platforms for mGlu1 receptor-mediated calcium signaling in association with caveolin

The actions of volatile anesthetics: a new perspective

Quantitative Profiling of Brain Lipid Raft Proteome in a Mouse Model of Fragile X Syndrome

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