Mechanism of arachidonic acid action on syntaxin–Munc18

Connell, Emma; Darios, Frédéric; Broersen, Kerensa; Gatsby, N; Peak‐Chew, Sew‐Yeu; Rickman, Colin; Davletov, Bazbek

doi:10.1038/sj.embor.7400935

Cited by 84 publications

(89 citation statements)

References 33 publications

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“…For example, titration studies demonstrated the ability of Munc18 to displace SNAP25 and VAMP2 from syntaxin 1, coordinate with the ability to co-immunoprecipitate only syntaxin 1 with anti-Munc18 antibody but not SNAP25 or VAMP2 from detergent-solubilized (1% Triton X-100) synaptosomal membranes (24,33,46). However, more recent studies show that although the Munc18-syntaxin binary complex does predominate, under in vitro conditions containing little (0.1% Triton X-100) or no detergent, SNARE complexes bound by Munc18 were detected (27,28,51,57). Using a novel immunofluorescent approach, it was shown that syntaxin 1 bound to Munc18-1 could also bind SNAP25 but that the addition of VAMP2 displaced Munc18-1 (39).…”

Section: Discussionmentioning

confidence: 94%

The Tyrosine Phosphorylation of Munc18c Induces a Switch in Binding Specificity from Syntaxin 4 to Doc2β

Jewell

Bennett

et al. 2008

Journal of Biological Chemistry

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Glucose-stimulated insulin secretion is mediated by syntaxin 4-based SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein complexes and the Sec1/ Munc18 protein Munc18c. Our laboratory recently reported that Munc18c-syntaxin 4 complexes are further regulated by the competitive binding of the double C2 domain protein Doc2␤ to Munc18c, although the underlying mechanism for this is unknown. Because the Doc2␤ binding region of Munc18c contained residue Tyr-219 and this residue becomes phosphorylated in response to glucose stimulation, we hypothesized that the mechanism would involve Munc18c phosphorylation. Coimmunoprecipitation analyses using detergent lysates prepared from pervanadate-treated MIN6 beta cells revealed that the tyrosine phosphorylation of Munc18c corresponded to a 60% decrease in Glucose homeostasis requires "cross-talk" between insulin signaling in peripheral tissues (adipose and muscle) and insulin secretion from pancreatic islet beta cells. Both glucose uptake and insulin secretion are mediated by syntaxin 4-based SNARE 2 protein complexes (1, 2). The vesicle-associated SNARE protein (VAMP2) is functional in both glucose uptake and insulin granule exocytosis processes and complexes with the binary cognate receptor complex at the target membrane composed of SNAP23 and syntaxin 4 proteins (t-SNAREs) to form a SNARE heterotrimeric complex (3-11). This SNARE core complex is further regulated by the Munc18c isoform of the Sec1/Munc18 secretory protein family through its ability to directly bind to syntaxin 4 at the plasma membrane (8,(12)(13)(14)(15)(16)(17)(18)(19)(20). Although genetic models of Munc18c over-expression (12) and under-expression (13, 21) have both unequivocally substantiated Munc18c as a key and physiologically relevant regulator of glucose homeostasis by its impact upon syntaxin 4-mediated exocytosis, its precise role as a negative or positive factor in the molecular mechanism has remained unresolved. Evidence in favor of Munc18c as a negative regulator of exocytosis is principally based upon over-expression methodologies but was supported by crystallographic and NMR data showing that the neuronal Munc18 protein (nSec1/Munc18-1/ Munc18a) held its syntaxin 1 binding partner in a closed conformation in a 1:1 stoichiometric complex (22, 23) and in vitro protein-protein interaction studies stating the absence of Munc18 from the 7 S and 20 S SNARE complexes (24, 25). The role of Munc18c as a possible positive regulator in exocytosis is based upon aberrant glucose uptake and insulin secretion from Munc18c heterozygous knock-out mice and peptide interference of endogenous Munc18c-syntaxin 4 association in 3T3L1 adipocytes (13,20). In addition, recent in vitro data have detected Sec1/Munc18 proteins associated with SNARE core complexes (26 -29). Notably, these recent in vitro studies were conducted using milder detergent conditions than earlier studies that showed Sec1/Munc18 protein binding to monomeric syntaxin in cell lysates (30 -33). These differing buf...

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Section: Discussionmentioning

confidence: 94%

The Tyrosine Phosphorylation of Munc18c Induces a Switch in Binding Specificity from Syntaxin 4 to Doc2β

Jewell

Bennett

et al. 2008

Journal of Biological Chemistry

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“…Previous reports showed that cPLA 2 activity modifies the transport of several proteins between Golgi vesicles and plasma membranes in nonneuronal cell types (Choukroun et al, 2000;Regan-Klapisz et al, 2009). Taking this into account along with the role of AA in Munc18-syntaxin interactions (Connell et al, 2007) and the influence of cPLA 2 on membrane organization and lipid vesicles formation (Gubern et al, 2008), it is tempting to speculate that A␤-activated cPLA 2 1123.e25could surrogate the transportation of synaptic proteins into various lipid compartments.…”

Section: Discussionmentioning

confidence: 98%

“…The presynaptic proteins synaptophysin and synaptotagmin are involved in the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes with several other partners such as syntaxin-1 and Munc18. AA stabilizes interactions between Munc18, syntaxin-1 and synaptosomal-associated protein, 25 kDa (SNAP25), thus favoring exocytosis of neurotransmitters (Connell et al, 2007;Latham et al, 2007). Increase in free AA released by cPLA 2 in response to A␤ oligomers could therefore be involved in synaptic dysfunctions.…”

Section: Discussionmentioning

confidence: 99%

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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Soluble beta-amyloid (A␤) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that A␤ oligomers activate cytosolic phospholipase A 2 (cPLA 2 ), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA 2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of A␤ oligomers in wild type mice. We further demonstrated that the A␤ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA 2 Ϫ/Ϫ mice. Interestingly, expression of the A␤ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA 2 Ϫ/Ϫ mice, but the relationship with the resistance of these mice to the A␤ oligomer toxicity requires further investigation. These results therefore show that cPLA 2 plays a key role in the A␤ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.

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“…Moreover, depletion of the cPLA 2 product, arachidonic acid, has been shown to inhibit STX4 from forming SNARE complexes (Connell et al, 2007). Arachidonic acid induces the so-called 'syntaxin-opened' conformation that is required for SNARE assembly (Connell et al, 2007;Rickman and Davletov, 2005), further supporting the involvement of cPLA 2 in the modulation of syntaxins that participate in SNARE trafficking and assembly.…”

Section: Loss Of Npc1 Interferes With Cholesterol-sensitive Vesicle Fmentioning

confidence: 95%

Role of cholesterol in SNARE-mediated trafficking on intracellular membranes

Enrich

Rentero

Hierro

et al. 2015

Journal of Cell Science

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The cell surface delivery of extracellular matrix (ECM) and integrins is fundamental for cell migration in wound healing and during cancer cell metastasis. This process is not only driven by several soluble NSF attachment protein (SNAP) receptor (SNARE) proteins, which are key players in vesicle transport at the cell surface and intracellular compartments, but is also tightly modulated by cholesterol. Cholesterol-sensitive SNAREs at the cell surface are relatively well characterized, but it is less well understood how altered cholesterol levels in intracellular compartments impact on SNARE localization and function. Recent insights from structural biology, protein chemistry and cell microscopy have suggested that a subset of the SNAREs engaged in exocytic and retrograde pathways dynamically 'sense' cholesterol levels in the Golgi and endosomal membranes. Hence, the transport routes that modulate cellular cholesterol distribution appear to trigger not only a change in the location and functioning of SNAREs at the cell surface but also in endomembranes. In this Commentary, we will discuss how disrupted cholesterol transport through the Golgi and endosomal compartments ultimately controls SNARE-mediated delivery of ECM and integrins to the cell surface and, consequently, cell migration.

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Mechanism of arachidonic acid action on syntaxin–Munc18

Cited by 84 publications

References 33 publications

The Tyrosine Phosphorylation of Munc18c Induces a Switch in Binding Specificity from Syntaxin 4 to Doc2β

The Tyrosine Phosphorylation of Munc18c Induces a Switch in Binding Specificity from Syntaxin 4 to Doc2β

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Role of cholesterol in SNARE-mediated trafficking on intracellular membranes

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