CaM kinase IIα mediates norepinephrine-induced translocation of cytosolic phospholipase A2 to the nuclear envelope

Fatima, Soghra; Yaghini, Fariborz A.; Ahmed, Aftab; Khandekar, Zinat; Malik, Kafait U.

doi:10.1242/jcs.00242

Cited by 31 publications

(24 citation statements)

References 61 publications

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“…As shown in Fig. 2A, TCDD triggered a marked and transient increase of CaMK activity, which reached levels similar to those observed in response to norepinephrine, a well known activator of CaMK activity (Fatima et al, 2003). Chemical inhibition of the Ca 2ϩ / CaM/CaMK signaling pathway using either the CaMK inhibitor KN-93 or the CaM antagonist W7 was next found to counteract TCDD-mediated induction of CYP1A1 activity (Fig.…”

Section: Tcdd-mediated Cyp1a1 Up-regulation Was Impaired By Chemical supporting

confidence: 61%

Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway

Monteiro

Gilot²,

Ferrec

et al. 2007

Mol Pharmacol

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Section: Tcdd-mediated Cyp1a1 Up-regulation Was Impaired By Chemical supporting

confidence: 61%

Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway

Monteiro

Gilot²,

Ferrec

et al. 2007

Mol Pharmacol

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“…In MDCK cells, cPLA 2 mutants S505A and S727A were translocated to the Golgi in a similar manner as wild-type cPLA 2 in response to ATP and ionomycin (7). However, in VSMCs, the translocation of cPLA 2 to the nuclear envelope in response to NE was blocked by the CaMKII inhibitor KN-93, which attenuates the phosphorylation of cPLA 2 at S515 (25). This suggests that inhibition of CaMKII by KN93 blocks some additional signaling event triggered by CaMKII activation that is required for cPLA 2 translocation.…”

Section: Discussionmentioning

confidence: 97%

cPLA2 phosphorylation at serine-515 and serine-505 is required for arachidonic acid release in vascular smooth muscle cells

Pavicevic

Leslie

Malik

2008

Journal of Lipid Research

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Cytosolic phospholipase A 2 (cPLA 2 ) is activated by phosphorylation at serine-505 (S505) by extracellular regulated kinase 1/2 (ERK1/2). However, rat brain calcium/ calmodulin-dependent kinase II (CaMKII) phosphorylates recombinant cPLA 2 at serine-515 (S515) and increases its activity in vitro. We have studied the sites of cPLA 2 phosphorylation and their significance in arachidonic acid (AA) release in response to norepinephrine (NE) in vivo in rabbit vascular smooth muscle cells (VSMCs) using specific anti-phospho-S515-and -S505 cPLA 2 antibodies and by mutagenesis of S515 and S505 to alanine. NE increased the phosphorylation of cPLA 2 at S515, followed by phosphorylation of ERK1/2 and consequently phosphorylation of cPLA 2 at S505. The CaMKII inhibitor 2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzene-sulfonyl)]amino-N-(4-chlorocinnamyl)-methylbenzylamine attenuated cPLA 2 at S515 and S505, whereas the ERK1/2 inhibitor U0126 reduced phosphorylation at S505 but not at S515. NE in cells transduced with adenovirus carrying enhanced cyan fluorescent protein cPLA 2 wild type caused phosphorylation at S515 and S505 and increased AA release. Expression of the S515A mutant in VSMCs reduced the phosphorylation of S505, ERK1/2, and AA release in response to NE. Transduction with a double mutant (S515A/S505A) blocked the phosphorylation of cPLA 2 and AA release. These data suggest that the NE-stimulated phosphorylation of cPLA 2 at S515 is required for the phosphorylation of S505 by ERK1/2 and that both sites of phosphorylation are important for AA release in VSMCs.-Pavicevic, Z., C. C. Leslie, and K. U. Malik. cPLA 2 phosphorylation at serine-515 and serine-505 is required for arachidonic acid release in vascular smooth muscle cells. Norepinephrine (NE) released from postganglionic sympathetic fibers stimulates arachidonic acid (AA) release for the synthesis of prostaglandins, which, in turn, act as a physiological modulator of neurotransmitter release in various tissues, including blood vessels (1). In vascular smooth muscle cells (VSMCs), NE stimulates the release of AA via the a1-adrenergic receptor by the activation of cytosolic phospholipase A 2 (cPLA 2 ) (2, 3), a group IV phospholipase A 2 member (4). NE-induced cPLA 2 activation and AA release require calcium (Ca 21 ), calmodulin (CaM), and calmodulin-dependent kinase II (CaMKII) in VSMCs (2, 3). cPLA 2 activity has been reported to be regulated by phosphorylation by extracellular regulated kinase 1/2 (ERK1/2), p42/p44 mitogen-activated protein kinase, and Ca 21-dependent translocation to the nuclear envelope, allowing its access to arachidonyl-containing phospholipid substrate at the sn-2 position (6). ERK1/2 phosphorylates cPLA 2 at serine-505 (S505) in several cell types (5-7). However, the phosphorylation and activation of cPLA 2 by a mechanism independent of ERK1/2 has also been reported (8) and may be mediated by other members of the mitogenactivated protein kinase family, such as p38 stress-activated protein kinase (9, 10). The existence of multiple...

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“…Some isoforms of PLA 2 translocate from the cytosol to the NE (59), where enzymes of eicosanoid generation are clustered (60). Isolated nuclei from LA-N-1 cells carried out synthesis of PtdCho, an activity that was enhanced by phorbol ester (14).…”

Section: Lipid-metabolizing Enzymes and Lipid Signaling In The Nucleusmentioning

confidence: 99%

Nuclear lipids: key signaling effectors in the nervous system and other tissues

Ledeen

2004

Journal of Lipid Research

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Lipids have long been recognized as quantitatively minor components of the nucleus, where they were initially thought to have little functional importance; but they now command growing interest, with recognition of their diverse signaling and modulating properties in that organelle. This applies to the lipid-poor compartments of the nucleoplasm as well as the relatively lipid-rich nuclear envelope. Phosphoglycerides and sphingomyelin, as the predominant lipids, have attracted the most interest among researchers, but some of the less-abundant lipids such as gangliosides, sphingosine, and sphingosine phosphate are now becoming recognized as functionally important nuclear constituents. Among recent advances in this emerging field are detailed findings on the metabolic enzymes that synthesize and catabolize nuclear lipids; the fact that these are localized primarily within the nucleus itself indicates considerable autonomy with respect to lipid metabolism. Current studies suggest several key processes involving RNA and DNA reactivity that are dependent on these lipid-initiated events. Neural cell nuclei have been the subject of such investigations, with results that closely parallel the more numerous studies on nuclei of extraneural cells. This review attempts to outline some of the major findings on nuclear lipids of diverse cell types; results with nonneural nuclei will hopefully provide useful guideposts to further studies of neural systems. -Ledeen, R. W., and G. Wu. Lipids are integral components of the nuclei from all cells examined to date, including those of the nervous system. Their function in that organelle was originally considered to be merely one of structural support for the nuclear envelope (NE), perhaps reflecting their relative paucity in other nuclear compartments. However, this concept has changed dramatically in the last decade or two with growing awareness of lipid presence in the various domains of the nucleoplasm and recognition of the powerful signaling and modulating roles of lipids and their metabolic products in all nuclear compartments. Although there have been relatively few systematic comparisons of nuclear lipids of different tissues and species, similar properties and derived mechanisms appear to apply in broad outline regardless of cellular origin. Lipid metabolism in the nucleus is now recognized as largely autonomous, although certain extracellular stimuli are able to induce lipid signaling in the nucleus only (1, 2) or in the nucleus as well as cytoplasm (3,4). Early studies emphasized phospholipids (PLs), the predominant lipids of nuclei, and while that is still the major thrust of current research, other less-abundant lipids such as gangliosides and sphingosine/sphingosine phosphate are gaining recognition as nuclear constituents with important functional roles. Cholesterol occurs in the outer nuclear membrane (ONM), presumably in a structural role, and may also be present in a few select nucleoplasmic domains. This review will attempt to summarize some of the major fi...

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CaM kinase IIα mediates norepinephrine-induced translocation of cytosolic phospholipase A2 to the nuclear envelope

Cited by 31 publications

References 61 publications

Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway

Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway

cPLA2 phosphorylation at serine-515 and serine-505 is required for arachidonic acid release in vascular smooth muscle cells

Nuclear lipids: key signaling effectors in the nervous system and other tissues

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