Human adenosine A3 receptor leads to intracellular Ca2+ mobilization but is insufficient to activate the signaling pathway via phosphoinositide 3-kinase γ in mice

Yamano, Kazuya; Inoue, Miho; Masaki, Shigehiro; Saki, Mayumi; Ichimura, Michio; Satoh, Mitsuo

doi:10.1016/j.bcp.2005.08.003

Cited by 16 publications

(15 citation statements)

References 36 publications

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“…Previous study shows that A3AR activation induces an increase in intracellular Ca 2? via specific G protein-coupled receptors [22,23]. Therefore, Cl-IB-MECA may induce cell death through an increase in intracellular Ca 2?…”

Section: Discussionmentioning

confidence: 98%

The Adenosine A3 Receptor Agonist Cl-IB-MECA Induces Cell Death Through Ca2+/ROS-Dependent Down Regulation of ERK and Akt in A172 Human Glioma Cells

Kim

Woo

2012

Neurochem Res

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Adenosine A(3) receptor (A3AR) is coupled to G proteins that are involved in a variety of intracellular signaling pathways and physiological functions. 2-Chloro-N(6)-(3-iodobenzyl) adenosine-5'-N-methylcarboxamide (Cl-IB-MECA), an agonist of A3AR, has been reported to induce cell death in various cancer cells. However, the effect of CI-IB-MECA on glioma cell growth is not clear. This study was undertaken to examine the effect of CI-IB-MECA on glioma cell viability and to determine its molecular mechanism. CI-IB-MECA inhibited cell proliferation and induced cell death in a dose- and time-dependent manner. Treatment of CI-IB-MECA resulted in an increase in intracellular Ca(2+) followed by enhanced reactive oxygen species (ROS) generation. EGTA and N-acetylcysteine (NAC) blocked the cell death induced by CI-IB-MECA, suggesting that Ca(2+) and ROS are involved in the Cl-IB-MECA-induced cell death. Western blot analysis showed that CI-IB-MECA induced the down-regulation of extracellular signal-regulated kinases (ERK) and Akt, which was prevented by EGTA, NAC, and the A3AR antagonist MRS1191. Transfection of constitutively active forms of MEK, the upstream kinase of ERK, and Akt prevented the cell death. CI-IB-MECA induced caspase-3 activation and the CI-IB-MECA-induced cell death was blocked by the caspase inhibitors DEVD-CHO and z-VAD-FMK. In addition, expression of XIAP and Survivin were decreased in cells treated with Cl-IB-MECA. Collectively, these findings demonstrate that CI-IB-MECA induce a caspase-dependent cell death through suppression of ERK and Akt mediated by an increase in intracellular Ca(2+) and ROS generation in human glioma cells. These suggest that A3AR agonists may be a potential therapeutic agent for induction of apoptosis in human glioma cells.

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Section: Discussionmentioning

confidence: 98%

The Adenosine A3 Receptor Agonist Cl-IB-MECA Induces Cell Death Through Ca2+/ROS-Dependent Down Regulation of ERK and Akt in A172 Human Glioma Cells

Kim

Woo

2012

Neurochem Res

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“…Thus, In the mouse and rat, it is the G i -linked A 3 receptor that appears to be the major receptor involved in the ability of adenosine to enhance FcεRI-mediated degranulation [75]. However, in the human, the A 3 receptor does not appear to be involved in the regulation of degranulation [76], thus, the ability of adenosine to upregulate degranulation in the human appers to be primarily via the A 2B adenosine receptor. …”

mentioning

confidence: 99%

G protein-coupled receptors and the modification of FcɛRI-mediated mast cell activation

2007

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By releasing multiple pro-inflammatory mediators upon activation, mast cells are critical effector cells in the pathogenesis of allergic inflammation. The traditional viewpoint of antigen-dependent mast cell activation is that of a Th 2 -driven process whereby antigen-specific IgE molecules are produced by B cells followed by binding of the IgE to high affinity IgE receptors (FcεRI) expressed on mast cells. Subsequent antigen-dependent aggregation of the FcεRI initiates an intracellular signalling cascade that culminates in mediator release. Mast cell responses, including cell growth, survival, chemotaxis, and cell adhesion, however, can also be regulated by other receptors expressed on mast cells. Furthermore, FcεRI-mediated mast cell mediator release can be significantly modified by ligation of specific classes of these receptors. One such class of receptors is the G protein-coupled receptors (GPCR). In this review, we describe how sub-populations of GPCRs can either enhance or inhibit FcεRI-mediated mast cell activation depending on the particular G protein utilized for relaying signalling. Furthermore, we discuss the potential mechanisms whereby the signalling responses utilized by the FcεRI for mast cell activation are influenced by those initiated by GPCRs to produce these diverse responses. KeywordsMast cells; FcεRI; G protein-coupled receptors; IgE; antigen; signalling Mast cell activationMast cells play a role in both the innate and adaptive immune responses which contribute to the body's defence mechanisms against invading pathogens and parasites [1][2][3]. However, when mast cells are inappropriately activated following antigen exposure, the resulting release of multiple pro-inflammatory mediators leads to the initiation of the clinical manifestations associated with allergic inflammation [4]. This response occurs as a consequence of the antigen binding to IgE molecules which occupy high affinity receptors for IgE (FcεRI) on the mast cell surface and resulting cross-linking of these receptors [5,6]. FcεRI aggregation induces a cascade of intracellular signalling events which lead to the rapid release of histamine and proteolytic enzymes, as a consequence of degranulation, and the release of leukotrienes (LTs) and prostaglandins (PGs), as a result of phospholipase A 2 (PLA 2 )-mediated phospholipid hydrolysis [4,7]. Following enhanced gene expression, a variety of cytokines and chemokines * To whom correspondence be addressed: agilfillan@niaid.nih.gov, Bldg 10, Room 11C206, LAD, NIAID, NIH, 10 Center Drive, Bethesda, USA, MD 20892-1881, Phone: 301 496 8757, Fax: 301 480 8384. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the...

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“…These results therefore implicated Gi protein(s), phosphatidylinositol 3 kinase (PI3K) and presumably phospholipase Cβ (PLCβ) as principal mediators of A3R stimulated degranulation in murine lung MCs. Ca 2+ rise, PI3K as well as ERK activation were also noted in BMMCs, whose FcεRI-induced release of mediators was potentiated by the A3R (Yamano et al, 2005, 2006). Finally, studies in RBL-2H3 cells demonstrated A3R stimulated and Ptx sensitive activation of PLC (Ramkumar et al, 1993) and PLD (Ali et al, 1996), rise in Ca 2+ , and activation of PI3K/Akt (Gao et al, 2001).…”

Section: A3r Signaling In Rodent and Human Mcsmentioning

confidence: 95%

“…In a similar fashion, intravenous application of N 6-2-(4-aminophenyl)ethyladenosine (APNEA; Fozard et al, 1996) or intradermal introduction of the A3R agonist 2-(1-Hexynyl)- N -methyladenosine (IB-MECA; Reeves et al, 1997) to rats, respectively induced MC degranulation or plasma protein extravasation (PPE), confirming a key role for the A3R in mediating MCs responses. However, exposure of rat isolated pleural MCs, RBL-2H3 cells, or BMMCs to IB-MECA, enhanced FcεRI-induced secretion, but failed to induce directly such degranulation (Ramkumar et al, 1993; Reeves et al, 1997; Yamano et al, 2005, 2006). Therefore, collectively these studies have firmly established the involvement of the A3R in MC degranulation.…”

Section: The A3r As Mediator Of Mcs-dependent Inflammationmentioning

confidence: 99%

“…Though not tested, it is tempting to speculate that the lack of activation of PLCβ by the A3R in the HMC-1 cells prevents them from degranulation and restricts this receptor function to the induction of gene up-regulation and possibly the generation of arachidonic acid metabolites (Figure 2). Interestingly, exploring the signaling patterns of the A3R in BMMCs derived from a humanized mouse, in which the mouse A3R gene was replaced by its human counterpart, revealed that A3R activation evoked a Ptx sensitive rise in Ca 2+ , but failed to enhance ERK1/2 or Akt phosphorylation, which are stimulated by the murine A3R (Yamano et al, 2005). These results led the authors to conclude that the hA3R couples to different G-proteins for Ca 2+ mobilization and PI3K/ERK1/2 activation (Yamano et al, 2005).…”

Section: A3r Signaling In Rodent and Human Mcsmentioning

confidence: 99%

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Mast Cell Adenosine Receptors Function: A Focus on the A3 Adenosine Receptor and Inflammation

Rudich¹,

Ravid²,

Sagi‐Eisenberg³

2012

Front. Immun.

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Adenosine is a metabolite, which has long been implicated in a variety of inflammatory processes. Inhaled adenosine provokes bronchoconstriction in asthmatics or chronic obstructive pulmonary disease patients, but not in non-asthmatics. This hyper responsiveness to adenosine appears to be mediated by mast cell activation. These observations have marked the receptor that mediates the bronchoconstrictor effect of adenosine on mast cells (MCs), as an attractive drug candidate. Four subtypes (A1, A2a, A2b, and A3) of adenosine receptors have been cloned and shown to display distinct tissue distributions and functions. Animal models have firmly established the ultimate role of the A3 adenosine receptor (A3R) in mediating hyper responsiveness to adenosine in MCs, although the influence of the A2b adenosine receptor was confirmed as well. In contrast, studies of the A3R in humans have been controversial. In this review, we summarize data on the role of different adenosine receptors in mast cell regulation of inflammation and pathology, with a focus on the common and distinct functions of the A3R in rodent and human MCs. The relevance of mouse studies to the human is discussed.

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Human adenosine A3 receptor leads to intracellular Ca2+ mobilization but is insufficient to activate the signaling pathway via phosphoinositide 3-kinase γ in mice

Cited by 16 publications

References 36 publications

The Adenosine A3 Receptor Agonist Cl-IB-MECA Induces Cell Death Through Ca2+/ROS-Dependent Down Regulation of ERK and Akt in A172 Human Glioma Cells

The Adenosine A3 Receptor Agonist Cl-IB-MECA Induces Cell Death Through Ca2+/ROS-Dependent Down Regulation of ERK and Akt in A172 Human Glioma Cells

G protein-coupled receptors and the modification of FcɛRI-mediated mast cell activation

Mast Cell Adenosine Receptors Function: A Focus on the A3 Adenosine Receptor and Inflammation

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