The Ca2+-sensing Receptor Activates Cytosolic Phospholipase A2 via a Gqα-dependent ERK-independent Pathway

Handlogten, Mary E.; Huang, Changcheng; Shiraishi, Naoki; Awata, Hisataka; Miller, R. Tyler

doi:10.1074/jbc.m007306200

Cited by 87 publications

(57 citation statements)

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“…After the completion of our studies, Handlogten et al (36) reported that cPLA 2 is activated in human embryonic kidney 293 cells that have been transfected with the calcium-sensing receptor in a MAP kinase-independent way involving Gq, phospholipase C, Ca 2ϩ -CaM, and CaM kinase II (as shown by transfection studies and use of a CaM kinase II inhibitor) (36). It would be interesting to determine the site(s) of cPLA 2 phosphorylation in these cells.…”

Section: Discussionmentioning

confidence: 99%

Functional Interaction of Calcium-/Calmodulin-dependent Protein Kinase II and Cytosolic Phospholipase A2

Muthalif

Hefner

Canaan

et al. 2001

Journal of Biological Chemistry

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on Ser-515, but not on Ser-505 or Ser-727, occurs in vivo. This novel signaling pathway for arachidonate release is shown to be cPLA 2 -dependent by use of a recently described and highly selective inhibitor of this enzyme.Many cellular stimuli produce oscillations in the intracellular concentration of Ca 2ϩ . Ca 2ϩ -/calmodulin (CaM) 1 -dependent kinase II (CaM kinase II), a multifunctional protein kinase, decodes the frequency of Ca 2ϩ spikes and regulates the activity of a range of cellular targets involved in many physiological processes including control of cell cycle, apoptosis, gene expression, neurotransmission, synaptic plasticity, learning and memory, and early after-depolarization (1, 2).We have shown previously that the adrenergic transmitter norepinephrine (NE) and angiotensin II increase CaM kinase II activity in vascular smooth muscle cells (VSMC), leading to activation of cytosolic phospholipase A 2 (cPLA 2 ) (3-5). cPLA 2 liberates arachidonic acid by hydrolyzing arachidonyl phospholipids (6, 7). Arachidonic acid is the precursor of a variety of lipid mediators including leukotrienes and prostaglandins that modulate a number of cellular processes (8). cPLA 2 is an attractive target for the development of novel therapies because of its profound role in inflammatory processes, allergic responses, reproductive physiology, post-ischemic brain injury, cell proliferation, and cancer (9 -13).cPLA 2 is activated in a variety of cell types by growth factors, neurotransmitters, angiotensin II, vasopressin, lipopolysaccharides, colony-stimulating factor-1, thrombin, and other agonists (6,14,15). cPLA 2 , like protein kinase C, GTPase-activating proteins, phospholipase C, and p65, contains a Ca 2ϩ -dependent phospholipid binding domain that mediates translocation of cPLA 2 to the nuclear envelope and perinuclear region of cells (16 -18). cPLA 2 is regulated post-translationally by submicromolar Ca 2ϩ and phosphorylation (6, 19). p42/p44 mitogen-activated protein (MAP) kinase phosphorylate cPLA 2 on Ser-505 in many cell types (6, 20), whereas other members of the MAP kinase family, namely p38 stress-activated protein kinases, phosphorylate cPLA 2 in platelets (21). Rigorous studies to map the phosphorylation sites on cPLA 2 have been carried out only with platelets, HeLa cells, and CHO cells, and these studies reveal that cPLA 2 is phosphorylated on . More recent work has shown that Ser-727 phosphorylation is catalyzed by MNK1 or a closely related isoform, which is a protein kinase that is activated by members of the MAP kinase family, and that both Ser-505 and Ser-727 phosphorylation are required for full activation of cPLA 2 (23). In most agonist/cell systems, cPLA 2 phosphorylation is not sufficient for its activation; a rise in intracellular Ca 2ϩ is also required, and Ca 2ϩ -independent cPLA 2 activation by an unknown mechanism has also been reported (6).We reported recently that in VSMC, cPLA 2 -catalyzed arachidonic acid release induced by NE or angiotensin II is significantly reduced by the CaM kinas...

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Section: Discussionmentioning

confidence: 99%

Functional Interaction of Calcium-/Calmodulin-dependent Protein Kinase II and Cytosolic Phospholipase A2

Muthalif

Hefner

Canaan

et al. 2001

Journal of Biological Chemistry

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“…1A) (20). This indicates that the regulation of CaR-coupled inositol lipid metabolism is G i -independent.…”

Section: Resultsmentioning

confidence: 81%

“…Thin layer chromatography (TLC) (LK5 silica gel 150 A) was purchased from Fisher Scientific. The anti-CaR antibody, HEK-293 stable cells expressing the wild type CaR or mutant CaR R796W , HA-CaR pcDNA3, and Myc-RGS4pCMV5 were described earlier (20,39). Myc-C 3 toxin pEF was generously provided by Dr. Sternweis (U.T.…”

Section: Methodsmentioning

confidence: 99%

“…CaR can stimulate G␣ i subunits to inhibit the activity of adenylyl cyclase (18) and activate extracellular signal-regulated protein kinase (ERK) (19). It activates members of the G␣ q subfamily to stimulate phospholipase C (PLC) that hydrolyzes phosphatidylinositol 4,5-bisphosphate (PI 4,5-P 2 ) to generate diacylglycerol (DAG) and inositol trisphosphate (IP 3 ) or increase intracellular Ca 2ϩ (Ca 2ϩ i ) (20). CaR activates a number of intracellular enzymes and kinases, including Src kinase, phospholipase A 2 , PLC, and phospholipase D in parathyroid and human embryonic kidney * This work was supported by grants from the American Heart Association (to C. F. H. and R. T. M.), the National Institutes of Health (DK-41726, to R. T. M.), and the Rainbow Center for Childhood PKD and Leonard Rosenberg Research Foundation.…”

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Parallel Activation of Phosphatidylinositol 4-Kinase and Phospholipase C by the Extracellular Calcium-sensing Receptor

Huang

Handlogten

Miller

2002

Journal of Biological Chemistry

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The calcium-sensing receptor (CaR) is a G proteincoupled receptor that regulates physiological processes including Ca 2؉ metabolism, Na ؉ , Cl ؊ , K ؉ , and H 2 0 balance, and the growth of some epithelial cells through diverse signaling pathways. Although many effects of CaR are mediated by the heterotrimeric G proteins G␣ q and G␣ i , not all signaling pathways regulated by CaR have been identified. We used human embryonic kidney (HEK)-293 cells that stably express human CaR to study the regulation of inositol lipid metabolism by CaR. The nonfunctional mutant CaR R796W was used as a negative control.

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“…IC 50 values reported for AACOCF 3 range from 5 to 50 mol/L for cPLA 2 and 0.5 to 15 mol/L for iPLA 2 . IC 50 reported for PACOCF 3 was 45 mol/L for cPLA 2 and 3 mol/L for iPLA 2 (Ackermann et al, 1995;Conde-Frieboes et al, 1996;Handlogten et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

Role of Cytoplasmic Phospholipase A₂ in Endothelium-Derived Hyperpolarizing Factor Dilations of Rat Middle Cerebral Arteries

You

Marrelli

Bryan

2002

J Cereb Blood Flow Metab

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Summary:Very little is known regarding the mechanism of action for the endothelium-derived hyperpolarizing factor (EDHF) response in cerebral vessels. The authors tested two hypotheses: (1) activation of the cytoplasmic form of phospholipase A 2 (cPLA 2 ) is involved with EDHF-mediated dilations in rat middle cerebral arteries; and (2) activation of the cPLA 2 involves an increase in endothelial Ca 2+ through activation of phospholipase C. Middle cerebral arteries were isolated from the rat, pressurized to 85 mm Hg, and luminally perfused. The EDHF response was elicited by luminal application of uridine triphosphate (UTP) after NO synthase and cyclooxygenase inhibition (10 −5 mol/L N-nitro-L-arginine methyl ester and 10 −5 mol/L indomethacin, respectively). AACOCF 3 and PACOCF 3 , inhibitors of cPLA 2 (Ca 2+ -sensitive) and Ca 2+ -insensitive PLA 2 (iPLA 2 ), dose dependently attenuated the EDHF response. A selective inhibitor for iPLA2, haloenol lactone suicide substrate, had no effect on the EDHF response. The EDHF response elicited by UTP was accompanied by an increase in endothelial Ca 2+ (144 to 468 nmol/L), and the EDHF dilation was attenuated with U73122, a phospholipase C inhibitor. The authors conclude that the EDHF response elicited by luminal UTP in rat middle cerebral arteries involved activation of phospholipase C, an increase in endothelial Ca 2+ , and activation of cPLA 2 .

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The Ca2+-sensing Receptor Activates Cytosolic Phospholipase A2 via a Gqα-dependent ERK-independent Pathway

Cited by 87 publications

References 38 publications

Functional Interaction of Calcium-/Calmodulin-dependent Protein Kinase II and Cytosolic Phospholipase A2

Functional Interaction of Calcium-/Calmodulin-dependent Protein Kinase II and Cytosolic Phospholipase A2

Parallel Activation of Phosphatidylinositol 4-Kinase and Phospholipase C by the Extracellular Calcium-sensing Receptor

Role of Cytoplasmic Phospholipase A₂ in Endothelium-Derived Hyperpolarizing Factor Dilations of Rat Middle Cerebral Arteries

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The Ca2+-sensing Receptor Activates Cytosolic Phospholipase A2 via a Gqα-dependent ERK-independent Pathway

Cited by 87 publications

References 38 publications

Functional Interaction of Calcium-/Calmodulin-dependent Protein Kinase II and Cytosolic Phospholipase A2

Functional Interaction of Calcium-/Calmodulin-dependent Protein Kinase II and Cytosolic Phospholipase A2

Parallel Activation of Phosphatidylinositol 4-Kinase and Phospholipase C by the Extracellular Calcium-sensing Receptor

Role of Cytoplasmic Phospholipase A2 in Endothelium-Derived Hyperpolarizing Factor Dilations of Rat Middle Cerebral Arteries

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Role of Cytoplasmic Phospholipase A₂ in Endothelium-Derived Hyperpolarizing Factor Dilations of Rat Middle Cerebral Arteries