Regulation of Cysteinyl Leukotriene Type 1 Receptor Internalization and Signaling

Naik, Snehal; Billington, Charlotte K.; Pascual, Rodolfo M.; Deshpande, Deepak A.; Stefano, Frank P.; Kohout, Trudy A.; Eckman, Delrae M.; Benovic, Jeffrey L.; Penn, Raymond B.

doi:10.1074/jbc.m413014200

Cited by 56 publications

(80 citation statements)

References 58 publications

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“…In contrast to data recently published using a recombinant receptor system (Naik et al, 2005), we found that PKC was not involved in agonist-induced CysLT 1 receptor desensitization in dU937 cells. On the contrary, GRKs seem to be involved in this process, considering that in a stable U937 clone with reduced GRK2 expression (Fernandez et al, 2002) the rate of recovery of CysLT 1 functionality was faster than that in control U937 cells, and a GRK2 inhibitor partially reduced agonist-induced desensitization.…”

Section: Discussioncontrasting

confidence: 56%

CysLT1 receptor is a target for extracellular nucleotide-induced heterologous desensitization: a possible feedback mechanism in inflammation

Capra

Ravasi

Accomazzo

et al. 2005

Journal of Cell Science

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Both cysteinyl-leukotrienes and extracellular nucleotides mediate inflammatory responses via specific G-protein-coupled receptors, the CysLT and the P2Y receptors, respectively. Since these mediators accumulate at sites of inflammation, and inflammatory cells express both classes of receptors, their responses are likely to be crossregulated. We investigated the molecular basis of desensitization and trafficking of the CysLT1 receptor constitutively and transiently expressed in the human monocyte/macrophage-like U937 or COS-7 cells in response to LTD4 or nucleotides. Exposure to agonist induced a rapid homologous desensitization of the CysLT1 receptor [as measured by the reduction in the maximal agonist-induced intracellular cytosolic Ca2+ ([Ca2+]i) transient], followed by receptor internalization (as assessed by equilibrium binding and confocal microscopy). Activation of P2Y receptors with ATP or UDP induced heterologous desensitization of the CysLT1 receptor. Conversely, LTD4-induced CysLT1 receptor activation had no effect on P2Y receptor responses, which suggests that the latter have a hierarchy in producing desensitizing signals. Furthermore, ATP/UDP-induced CysLT1 receptor desensitization was unable to cause receptor internalization, induced a faster recovery of CysLT1 functionality and was dependent upon protein kinase C. By contrast, homologous desensitization, which is probably dependent upon G-protein-receptor kinase 2 activation, induced a fast receptor downregulation and, accordingly, a slower recovery of CysLT1 functionality. Hence, CysLT1 receptor desensitization and trafficking are differentially regulated by the CysLT1 cognate ligand or by extracellular nucleotides. This crosstalk may have a profound physiological implication in the regulation of responses at sites of inflammation, and may represent just an example of a feedback mechanism used by cells to fine-tune their responses.

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Section: Discussioncontrasting

confidence: 56%

CysLT1 receptor is a target for extracellular nucleotide-induced heterologous desensitization: a possible feedback mechanism in inflammation

Capra

Ravasi

Accomazzo

et al. 2005

Journal of Cell Science

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“…Such observations are typical of GPCRs. However, unlike many studies of GPCR desensitization (45)(46)(47), G2A desensitization was not accompanied by obvious loss of the receptor from the cell surface; rather, desensitization to lyso-PL stimulation was temporally associated with visible G2A patching (Fig. 8), perhaps the result of progressive receptor self-association (Fig.…”

Section: Discussionmentioning

confidence: 94%

“…8; lyso-PC stimulation shown). Although receptor internalization has been reported as accompanying desensitization of many GPCRs following stimulation (45)(46)(47), the maintenance of elevated surface G2A through the period of functional desensitization suggested that G2A desensitization in neutrophils is more clearly associated with patching of the receptor than to its internalization. As such, we reasoned that any stimulus mobilizing secretory vesicles and patching G2A would lead to a nonresponsive state to subsequent lyso-PL stimulation.…”

Section: Lyso-pls Enhance Surface Localization and Redistribution Of mentioning

confidence: 99%

Lysophospholipids of Different Classes Mobilize Neutrophil Secretory Vesicles and Induce Redundant Signaling through G2A

Frasch

Berry²,

Murphy³

et al. 2007

The Journal of Immunology

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Lysophosphatidylcholine has been shown to enhance neutrophil functions through a mechanism involving the G protein-coupled receptor G2A. Recent data support an indirect effect of lysophosphatidylcholine on G2A rather than direct ligand binding. These observations prompted the hypothesis that other lysophospholipids (lyso-PLs) may also signal for human neutrophil activation through G2A. To this end, 1-oleoyl-2-hydroxy-sn-glycero-3-[phospho-l-choline], but also C18:1/OH lyso-PLs bearing the phosphoserine and phosphoethanolamine head groups, presented on albumin, were shown to signal for calcium flux in a self- and cross-desensitizing manner, implicating a single receptor. Blocking Abs to G2A inhibited calcium signaling by all three lyso-PLs. Furthermore, inhibition by both pertussis toxin and U-73122 established signaling via the Gαi/phospholipase C pathway for calcium mobilization. Altered plasma membrane localization of G2A has been hypothesized to facilitate signaling. Accordingly, an increase in detectable G2A was demonstrated by 1 min after lyso-PL stimulation and was followed by visible patching of the receptor. Western blotting showed that G2A resides in the plasma membrane/secretory vesicle fraction and not in neutrophil primary, secondary, or tertiary granules. Enhanced detection of G2A induced by lyso-PLs was paralleled by enhanced detection of CD45, confirming mobilization of the labile secretory vesicle pool. Together, these data show that lyso-PLs bearing various head groups redundantly mobilize G2A latent within secretory vesicles and result in G2A receptor/Gαi/phospholipase C signaling for calcium flux in neutrophils.

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“…Full-length A2B adenosine receptor internalizes via an arrestin-dependent pathway, but deep truncation of its C-terminus redirects it to an arrestin-independent route (Matharu et al, 2001). The cysteinyl leukotriene type 1 receptor internalizes normally in mouse embryonic fibroblasts in which both non-visual arrestins are knocked out, yet arrestin overexpression enhances its internalization (Naik et al, 2005), apparently linking it to an additional arrestin-dependent pathway, similar to the situation with the m2 mAChR . The metabotropic glutamate receptor mGluR1a undergoes extensive constitutive agonist-independent internalization that does not involve arrestins, yet its internalization in response to agonist is selectively mediated by arrestin2 (Dale et al, 2001).…”

Section: Does Arrestin Binding Predetermine the Internalization Pathway?mentioning

confidence: 99%

The structural basis of arrestin-mediated regulation of G-protein-coupled receptors

Gurevich

2006

Pharmacology & Therapeutics

406

446

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The 4 mammalian arrestins serve as almost universal regulators of the largest known family of signaling proteins, G-protein-coupled receptors (GPCRs). Arrestins terminate receptor interactions with G proteins, redirect the signaling to a variety of alternative pathways, and orchestrate receptor internalization and subsequent intracellular trafficking. The elucidation of the structural basis and fine molecular mechanisms of the arrestin-receptor interaction paved the way to the targeted manipulation of this interaction from both sides to produce very stable or extremely transient complexes that helped to understand the regulation of many biologically important processes initiated by active GPCRs. The elucidation of the structural basis of arrestin interactions with numerous nonreceptor-binding partners is long overdue. It will allow the construction of fully functional arrestins in which the ability to interact with individual partners is specifically disrupted or enhanced by targeted mutagenesis. These "custom-designed" arrestin mutants will be valuable tools in defining the role of various interactions in the intricate interplay of multiple signaling pathways in the living cell. The identification of arrestin-binding sites for various signaling molecules will also set the stage for designing molecular tools for therapeutic intervention that may prove useful in numerous disorders associated with congenital or acquired disregulation of GPCR signaling.

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Regulation of Cysteinyl Leukotriene Type 1 Receptor Internalization and Signaling

Cited by 56 publications

References 58 publications

CysLT1 receptor is a target for extracellular nucleotide-induced heterologous desensitization: a possible feedback mechanism in inflammation

CysLT1 receptor is a target for extracellular nucleotide-induced heterologous desensitization: a possible feedback mechanism in inflammation

Lysophospholipids of Different Classes Mobilize Neutrophil Secretory Vesicles and Induce Redundant Signaling through G2A

The structural basis of arrestin-mediated regulation of G-protein-coupled receptors

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