Ral and Phospholipase D2-Dependent Pathway for Constitutive Metabotropic Glutamate Receptor Endocytosis

Bhattacharya, Moshmi; Babwah, Andy V.; Godin, Christina M.; Anborgh, Pieter H.; Dale, Lianne B.; Poulter, Michael O.; Ferguson, Stephen S. G.

doi:10.1523/jneurosci.3155-04.2004

Cited by 83 publications

(59 citation statements)

References 45 publications

(73 reference statements)

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“…A relationship between the Ral GTPases and PLD was also described during regulated exocytosis (16), receptor endocytosis (33), and neurite branching (17). In the current study, RalA localized with PLD1 and PLD2 on nascent phagosomes, and the coimmunoprecipitation of RalA with the PLD isoforms under resting and stimulated conditions provides evidence that these proteins can interact in macrophages.…”

Section: Discussionsupporting

confidence: 72%

Ral Isoforms Are Implicated in FcγR-Mediated Phagocytosis: Activation of Phospholipase D by RalA

Corrotte

Nyguyen

Harlay

et al. 2010

The Journal of Immunology

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Phagocytosis is an essential element of the immune response permitting the elimination of pathogens, cellular debris, apoptotic cells, and tumor cells. Recently, both phospholipase D (PLD) isoforms, PLD1 and PLD2, were shown to be necessary for efficient FcγR-mediated phagocytosis. In this study, we investigated the role of a potential PLD regulator, the Ral GTPases RalA and RalB, in murine RAW 264.7 macrophages. Both Ral isoforms are expressed in macrophages and are transiently activated following FcγR stimulation. When Ral expression levels were varied using Ral mutants or interference RNA, phagocytosis assays revealed that Ral isoforms have antagonistic effects; RalA is a positive modulator, whereas RalB plays a negative role. We then focused on RalA and its possible relationship with PLD. The increase in PLD activity that occurs when phagocytosis is stimulated was inhibited in cells with reduced RalA protein, but it was unaffected by reduced levels of RalB. Furthermore, in macrophages transfected with dsRed-RalA and GFP-PLD1 or GFP-PLD2, RalA colocalized with PLD1 and PLD2 at the phagocytic cup during phagosome formation. Additional results obtained from immunoprecipitation of PLD from macrophages transfected with myc-RalA and hemagglutinin-tagged PLD1 or PLD2 indicated an enhanced interaction of RalA with both PLD isoforms during phagocytic stimulation. The increase in RalA and PLD1 interaction was transient and correlated with the time course of RalA activation. These findings reveal a novel pathway involving RalA and PLD in the regulation of FcγR-mediated phagocytosis.

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Section: Discussionsupporting

confidence: 72%

Ral Isoforms Are Implicated in FcγR-Mediated Phagocytosis: Activation of Phospholipase D by RalA

Corrotte

Nyguyen

Harlay

et al. 2010

The Journal of Immunology

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“…When transfected in HEK-293 cells, mGlu1␣ receptors are constitutively internalized, whereas cell surface expression of mGlu1␤ receptors remains stable (Pula et al, 2004). Constitutive internalization of mGlu1␣ receptors requires ␤-arrestins and clathrin (Pula et al, 2004) and is mediated by the small GTP-binding protein Ral, its guanine nucleotide exchange factor RalGDS (Ral GDP dissociation stimulator), and phospholipase D2, which is found to be associated with mGlu1 receptors under resting conditions (Bhattacharya et al, 2004).…”

Section: Mglu1 Structure and Functionmentioning

confidence: 99%

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Ferraguti

Crepaldi

Nicoletti³

2008

Pharmacol Rev

192

205

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Almost 25 years after the first report that glutamate can activate receptors coupled to heterotrimeric G-proteins, tremendous progress has been made in the field of metabotropic glutamate receptors. Now, eight members of this family of glutamate receptors, encoded by eight different genes that share distinctive structural features have been identified. The first cloned receptor, the metabotropic glutamate ( mGlu) receptor mGlu1 has probably been the most extensively studied mGlu receptor, and in many respects it represents a prototypical subtype for this family of receptors. Its biochemical, anatomical, physiological, and pharmacological characteristics have been intensely investigated. Together with subtype 5, mGlu1 receptors constitute a subgroup of receptors that couple to phospholipase C and mobilize Ca(2+) from intracellular stores. Several alternatively spliced variants of mGlu1 receptors, which differ primarily in the length of their C-terminal domain and anatomical localization, have been reported. Use of a number of genetic approaches and the recent development of selective antagonists have provided a means for clarifying the role played by this receptor in a number of neuronal systems. In this article we discuss recent advancements in the pharmacology and concepts about the intracellular transduction and pathophysiological role of mGlu1 receptors and review earlier data in view of these novel findings. The impact that this new and better understanding of the specific role of these receptors may have on novel treatment strategies for a variety of neurological and psychiatric disorders is considered

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“…Although mGlu1 receptors are internalized in a b-arrestin-dependent manner (Dale et al, 2001;Mundell et al, 2001;Iacovelli et al, 2003), there is little data showing this is the case for mGlu5 receptors. However, internalization of mGlu5 receptors can occur via clathrin-dependent (Bhattacharya et al, 2004) and clathrin-independent pathways (Fourgeaud et al, 2003). The former might be mediated by phospholipase D2, which recruits adaptor complexes of clathrin-coated pits.…”

Section: General Features Of Mglu5mentioning

confidence: 99%

Location-Dependent Signaling of the Group 1 Metabotropic Glutamate Receptor mGlu5

et al. 2014

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Although G protein-coupled receptors are primarily known for converting extracellular signals into intracellular responses, some receptors, such as the group 1 metabotropic glutamate receptor, mGlu5, are also localized on intracellular membranes where they can mediate both overlapping and unique signaling effects. Thus, besides "ligand bias," whereby a receptor's signaling modality can shift from G protein dependence to independence, canonical mGlu5 receptor signaling can also be influenced by "location bias" (i.e., the particular membrane and/or cell type from which it signals). Because mGlu5 receptors play important roles in both normal development and in disorders such as Fragile X syndrome, autism, epilepsy, addiction, anxiety, schizophrenia, pain, dyskinesias, and melanoma, a large number of drugs are being developed to allosterically target this receptor. Therefore, it is critical to understand how such drugs might be affecting mGlu5 receptor function on different membranes and in different brain regions. Further elucidation of the site(s) of action of these drugs may determine which signal pathways mediate therapeutic efficacy.

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Ral and Phospholipase D2-Dependent Pathway for Constitutive Metabotropic Glutamate Receptor Endocytosis

Cited by 83 publications

References 45 publications

Ral Isoforms Are Implicated in FcγR-Mediated Phagocytosis: Activation of Phospholipase D by RalA

Ral Isoforms Are Implicated in FcγR-Mediated Phagocytosis: Activation of Phospholipase D by RalA

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Location-Dependent Signaling of the Group 1 Metabotropic Glutamate Receptor mGlu5

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