The Cytosolic Phospholipase A2 Pathway, a Safeguard of β2-Adrenergic Cardiac Effects in Rat

Aït-Mamar, Bouziane; Cailleret, Michel; Rücker‐Martin, Catherine; Bouabdallah, A.; Candiani, Gabriele; Adamy, C.; Duvaldestin, P.; Pecker, Françoise; Defer, Nicole; Pavoine, Catherine

doi:10.1074/jbc.m410305200

Cited by 26 publications

(31 citation statements)

References 66 publications

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“…9). Overall, these results supported the notion that KSR1 coupled activated ERK1/2 selectively to its substrate, cPLA 2 , in response to signals generated at lipid rafts.…”

Section: Resultssupporting

confidence: 77%

“…Our results had demonstrated that Ras signals from lipid rafts regulated the phosphorylation of two ERK substrates, cPLA 2 and EGFr, and that KSR1 was the ERK scaffold mediating in cPLA 2 activation. As such, we questioned whether KSR1 also participated in ERK1/2 signals directed to EGFr, thus behaving as a "general" lipid raft scaffold.…”

Section: Resultsmentioning

confidence: 99%

“…11C), thereby pointing to IQGAP1 as the scaffold participating in the lipid raftinduced ERK signal, directed to this particular substrate. Since Ras signals derived from lipid rafts also regulated the activation of cPLA 2 , we tested whether IQGAP1 could also intervene in this a Distance between RSK1 and cPLA 2 particles. Immunogold electron microscopy was performed with NIH 3T3 cells.…”

Section: Resultsmentioning

confidence: 99%

“…These results demonstrated that ERK1/2 activated from different Ras signaling platforms selectively targeted distinct cytoplasmic substrates. To ascertain that ERK1/2 substrate selectivity was not altered by the levels of the targeted Ras proteins, we analyzed cPLA 2 and RSK1 activation in response to increasing concentrations of LCK-or CD8-RasV12. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Ras Subcellular Localization Defines Extracellular Signal-Regulated Kinase 1 and 2 Substrate Specificity through Distinct Utilization of Scaffold Proteins

Casar¹,

Arozarena

Sanz-Moreno

et al. 2009

Molecular and Cellular Biology

103

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Subcellular localization influences the nature of Ras/extracellular signal-regulated kinase (ERK) signals by unknown mechanisms. Herein, we demonstrate that the microenvironment from which Ras signals emanate determines which substrates will be preferentially phosphorylated by the activated ERK1/2. We show that the phosphorylation of epidermal growth factor receptor (EGFr) and cytosolic phospholipase A 2 (cPLA 2 ) is most prominent when ERK1/2 are activated from lipid rafts, whereas RSK1 is mainly activated by Ras signals from the disordered membrane. We present evidence indicating that the underlying mechanism of this substrate selectivity is governed by the participation of different scaffold proteins that distinctively couple ERK1/2, activated at defined microlocalizations, to specific substrates. As such, we show that for cPLA 2 activation, ERK1/2 activated at lipid rafts interact with KSR1, whereas ERK1/2 activated at the endoplasmic reticulum utilize Sef-1. To phosphorylate the EGFr, ERK1/2 activated at lipid rafts require the participation of IQGAP1. Furthermore, we demonstrate that scaffold usage markedly influences the biological outcome of Ras site-specific signals. These results disclose an unprecedented spatial regulation of ERK1/2 substrate specificity, dictated by the microlocalization from which Ras signals originate and by the selection of specific scaffold proteins.

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“…9). Overall, these results supported the notion that KSR1 coupled activated ERK1/2 selectively to its substrate, cPLA 2 , in response to signals generated at lipid rafts.…”

Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Ras Subcellular Localization Defines Extracellular Signal-Regulated Kinase 1 and 2 Substrate Specificity through Distinct Utilization of Scaffold Proteins

Casar¹,

Arozarena

Sanz-Moreno

et al. 2009

Molecular and Cellular Biology

103

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“…Simultaneously, PKA also phosphorylates the receptor and induces its coupling to G i . This coupling contributes also to the activation of cPLA 2 [as described by Aït-Mamar et al (1)] and to its positive control by PI3K. Because we found that the negative inotropic effect occurring at higher salbutamol concentrations (EC 50 in the submicromolar range) was sensitive only to H-89, L-NAME, and AACOCF 3 , we hypothesize that PKA-dependent phosphorylation of the receptor leads to activation of NOS independently of the G i -dependent PI3K/cPLA 2 pathway and that cPLA 2 exerts a negative control on this second pathway leading to NOS activation.…”

Section: Signaling Pathways Involvedmentioning

confidence: 99%

Roles of PKA, PI3K, and cPLA₂ in the NO-mediated negative inotropic effect of β₂-adrenoceptor agonists in guinea pig right papillary muscles

Faucher¹,

Gannier²,

Lignon³

et al. 2008

American Journal of Physiology-Cell Physiology

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Faucher FA, Gannier FE, Lignon JM, Cosnay P, Malécot CO. Roles of PKA, PI3K, and cPLA2 in the NO-mediated negative inotropic effect of ␤2-adrenoceptor agonists in guinea pig right papillary muscles. Am J Physiol Cell Physiol 294: C106-C117, 2008. First published October 17, 2007 doi:10.1152/ajpcell.00231.2007.-Although ␤2-adrenoceptors represent 15-25% of ␤-adrenoceptors in the guinea pig heart, their functionality is controversial. We assessed the inotropic effects of ␤2-adrenoceptor partial agonists in right papillary muscles. Salbutamol induced a small but significant concentration-dependent negative inotropic effect (NIE, Ϫ5% at 60 nM) followed by a moderate positive inotropic effect (ϩ36% at 6 M) due to activation of ␤ 1-adrenoceptors. In the presence of 4 M atenolol, the concentration-dependent NIE (Ϫ12% at 6 M) was biphasic, best described by a double logistic equation with respective EC50 values of 3 and ϳ420 nM, and was insensitive to SR59230A. In muscles from pertussis toxin-treated guinea pigs, the salbutamol-induced positive inotropic effect was sensitive to low concentrations of ICI-118551 in an unusual manner. Experiments in reserpinized animals revealed the importance of the phosphorylation-dephosphorylation processes. PKA inhibition reduced and suppressed the effects obtained at low and high concentrations, respectively, indicating that its activation was a prerequisite to the NIE. The effect occurring at nanomolar concentrations depended upon PKA/phosphatidylinositol 3-kinase/ cytosolic phospholipase A 2 (cPLA2) activations leading to nitric oxide (NO) release via the arachidonic acid/cyclooxygenase pathway. NO release via PKA-dependent phosphorylation of the receptor was responsible for the inotropic effect observed at submicromolar concentrations, which is negatively controlled by cPLA 2. The possibility that these effects are due to an equilibrium between different affinity states of the receptor (G s/Gi coupled and Gi independent with different signaling pathways) that can be displaced by ICI-118551 is discussed. We conclude that ␤ 2-adrenoceptors are functional in guinea pig heart and can modulate the inotropic state.salbutamol; ␤-adrenoceptor antagonists; cardiac contractility; G s/-Gi coupling; active conformations ␤-ADRENOCEPTORS play a fundamental role in the regulation of the cardiac contractile machinery, in part because of the predominance of sympathetic neuronal influences (45). In normal physiological conditions, cardiac stimulatory catecholamine effects are mostly mediated by ␤ 1 -adrenoceptors via their coupling to G s protein and activation of cAMP-dependent PKA signaling pathways. ␤ 2 -Adrenoceptors, although present at a lower density (the ␤ 1 -to ␤ 2 -adrenoceptor ratio in the human heart is ϳ70 -80%/30 -20%; Ref. 6), are more tightly coupled to the G s protein and thus induce a more pronounced activation of the adenylate cyclase (7). However, their inotropic effects are less than expected because of their localization in caveolae and the presence of a barrier of phosphodies...

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Lipid Signaling Pathways in the Heart

Marı́n-Garcı́a

2011

Signaling in the Heart

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The Cytosolic Phospholipase A2 Pathway, a Safeguard of β2-Adrenergic Cardiac Effects in Rat

Cited by 26 publications

References 66 publications

Ras Subcellular Localization Defines Extracellular Signal-Regulated Kinase 1 and 2 Substrate Specificity through Distinct Utilization of Scaffold Proteins

Ras Subcellular Localization Defines Extracellular Signal-Regulated Kinase 1 and 2 Substrate Specificity through Distinct Utilization of Scaffold Proteins

Roles of PKA, PI3K, and cPLA₂ in the NO-mediated negative inotropic effect of β₂-adrenoceptor agonists in guinea pig right papillary muscles

Lipid Signaling Pathways in the Heart

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The Cytosolic Phospholipase A2 Pathway, a Safeguard of β2-Adrenergic Cardiac Effects in Rat

Cited by 26 publications

References 66 publications

Ras Subcellular Localization Defines Extracellular Signal-Regulated Kinase 1 and 2 Substrate Specificity through Distinct Utilization of Scaffold Proteins

Ras Subcellular Localization Defines Extracellular Signal-Regulated Kinase 1 and 2 Substrate Specificity through Distinct Utilization of Scaffold Proteins

Roles of PKA, PI3K, and cPLA2 in the NO-mediated negative inotropic effect of β2-adrenoceptor agonists in guinea pig right papillary muscles

Lipid Signaling Pathways in the Heart

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Roles of PKA, PI3K, and cPLA₂ in the NO-mediated negative inotropic effect of β₂-adrenoceptor agonists in guinea pig right papillary muscles