The Experts below are selected from a list of 2787 Experts worldwide ranked by ideXlab platform
Shlomo Sasson - One of the best experts on this subject based on the ideXlab platform.
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regulation of glut4 activity in myotubes by 3 o methyl d glucose
Biochimica et Biophysica Acta, 2017Co-Authors: Guy Cohen, Arie Gruzman, Ofer Shamni, Hilal Zaid, Amira Klip, Erol Cerasi, Shlomo SassonAbstract:The rate of glucose influx to skeletal muscles is determined primarily by the number of functional units of glucose Transporter-4 (GLUT4) in the myotube plasma membrane. The abundance of GLUT4 in the plasma membrane is tightly regulated by insulin or contractile activity, which employ distinct pathways to translocate GLUT4-rich vesicles from intracellular compartments. Various studies have indicated that GLUT4 intrinsic activity is also regulated by conformational changes and/or interactions with membrane components and intracellular proteins in the vicinity of the plasma membrane. Here we show that the non-metabolizable glucose analog 3-O-methyl-d-glucose (MeGlc) augmented the rate of Hexose Transport into myotubes by increasing GLUT4 intrinsic activity without altering the content of the Transporter in the plasma membrane. This effect was not a consequence of ATP depletion or hyperosmolar stress and did not involve Akt/PKB or AMPK signal transduction pathways. MeGlc reduced the inhibitory potency (increased Ki) of indinavir, a selective inhibitor of GLUT4, in a dose-dependent manner. Kinetic analyses indicate that MeGlc induced changes in GLUT4 or GLUT4 complexes within the plasma membrane, which enhanced the Hexose Transport activity and reduced the potency of indinavir inhibition. Finally, we present a simple kinetic analysis for screening and discovering low molecular weight compounds that augment GLUT4 activity.
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Supportive data on the regulation of GLUT4 activity by 3-O-methyl-D-glucose
Elsevier, 2017Co-Authors: Ofer Shamni, Guy Cohen, Arie Gruzman, Hilal Zaid, Amira Klip, Erol Cerasi, Shlomo SassonAbstract:The data presented in this article are related to the research article entitled “Regulation of GLUT4 activity in myotubes by 3-O-methyl-D-glucose” (Shamni et al., 2017) [1]. These data show that the experimental procedures used to analyze the effects of 3-O-methyl-D-glucose (MeGlc) on the rate of Hexose Transport into myotubes were valid and controlled. The stimulatory effect of MeGlc was limited to glucose Transporter 4 (GLUT4) and was independent of ambient glucose and protein synthesis. Cornish-Bowden kinetic analysis of uptake data revealed that MeGlc attenuated indinavir-induced inhibition of Hexose Transport in a competitive manner
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adenosine monophosphate activated protein kinase ampk as a new target for antidiabetic drugs a review on metabolic pharmacological and chemical considerations
The review of diabetic studies : RDS, 2009Co-Authors: Arie Gruzman, Gali Babai, Shlomo SassonAbstract:In view of the epidemic nature of type 2 diabetes and the substantial rate of failure of current oral antidiabetic drugs the quest for new therapeutics is intensive. The adenosine monophosphate-activated protein kinase (AMPK) is an important regulatory protein for cellular energy balance and is considered a master switch of glucose and lipid metabolism in various organs, especially in skeletal muscle and liver. In skeletal muscles, AMPK stimulates glucose Transport and fatty acid oxidation. In the liver, it augments fatty acid oxidation and decreases glucose output, cholesterol and triglyceride synthesis. These metabolic effects induced by AMPK are associated with lowering blood glucose levels in hyperglycemic individuals. Two classes of oral antihyperglycemic drugs (biguanidines and thiazolidinediones) have been shown to exert some of their therapeutic effects by directly or indirectly activating AMPK. However, side effects and an acquired resistance to these drugs emphasize the need for the development of novel and efficacious AMPK activators. We have recently discovered a new class of hydrophobic D-xylose derivatives that activates AMPK in skeletal muscles in a non insulin-dependent manner. One of these derivatives (2,4;3,5-dibenzylidene-D-xylose-diethyl-dithioacetal) stimulates the rate of Hexose Transport in skeletal muscle cells by increasing the abundance of glucose Transporter-4 (GLUT-4) in the plasma membrane through activation of AMPK. This compound reduces blood glucose levels in diabetic mice and therefore offers a novel strategy of therapeutic intervention strategy in type 2 diabetes. The present review describes various classes of chemically-related compounds that activate AMPK by direct or indirect interactions and discusses their potential for candidate antihyperglycemic drug development.
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the roles of hyperglycaemia and oxidative stress in the rise and collapse of the natural protective mechanism against vascular endothelial cell dysfunction in diabetes
Archives of Physiology and Biochemistry, 2007Co-Authors: Guy Cohen, Yael Riahi, Evgenia Alpert, Arie Gruzman, Shlomo SassonAbstract:Vascular endothelial cell (VEC) dysfunction in diabetes has been associated with hyperglycaemia-induced intra- and extracellular glycation of proteins and to overproduction of glucose-derived free radicals. VEC protect their intracellular environment against an increased influx of glucose in face of hyperglycaemia by reducing the expression and plasma membrane abundance of their glucose Transporter-1 (GLUT-1). We investigated the hypothesis that glucose-derived free radicals induce this down-regulatory mechanism in VEC, but proved the contrary. In fact, pro-oxidants significantly increased the expression and plasma membrane abundance of GLUT-1 and the rate of glucose Transport in VEC while abolishing high-glucose-induced down-regulation of the Hexose Transport system. The resulting uncontrolled influx of glucose followed by overproduction of glucose-derived ROS further up-regulates the rate of glucose Transport, and vice versa. This perpetuating glycoxidative stress finally leads to the collapse of the auto-regulatory protective mechanism and accelerates the development of dysfunctional endothelium in blood vessels.
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a natural protective mechanism against hyperglycaemia in vascular endothelial and smooth muscle cells role of glucose and 12 hydroxyeicosatetraenoic acid
Biochemical Journal, 2002Co-Authors: Evgenia Alpert, Arie Gruzman, Hanan Totary, Nurit Kaiser, Reuven Reich, Shlomo SassonAbstract:Bovine aortic endothelial and smooth-muscle cells down-regulate the rate of glucose Transport in the face of hyperglycaemia, thus providing protection against deleterious effects of increased intracellular glucose levels. When exposed to high glucose concentrations these cells reduced the mRNA and protein content of their typical glucose Transporter, GLUT-1, as well as its plasma-membrane abundance. Inhibition of the lipoxygenase (LO) pathway, and particularly 12-LO, reversed this glucose-induced down-regulatory process and restored the rate of Hexose Transport to the level seen in vascular cells exposed to normal glucose levels. This reversal was accompanied by increased levels of GLUT-1 mRNA and protein, as well as of its plasma-membrane content. Exposure of the vascular cells to elevated glucose concentrations increased by 2-3-fold the levels of cell-associated and secreted 12-hydroxyeicosatetraenoic acid (12-HETE), the product of 12-LO. Inhibition of 15- and 5-LO, cyclo-oxygenases 1 and 2, and eicosanoid-producing cytochrome P450 did not modify the Hexose-Transport system in vascular cells. These results suggest a role for HETEs in the autoregulation of Hexose Transport in vascular cells. 8-Iso prostaglandin F(2alpha), a non-enzymic oxidation product of arachidonic acid, had no effect on the Hexose-Transport system in vascular cells exposed to hyperglycaemic conditions. Taken together, these findings show that hyperglycaemia increases the production rate of 12-HETE, which in turn mediates the down-regulation of GLUT-1 expression and the glucose-Transport system in vascular endothelial and smooth-muscle cells.
Michael P Czech - One of the best experts on this subject based on the ideXlab platform.
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an rna interference based screen identifies map4k4 nik as a negative regulator of pparγ adipogenesis and insulin responsive Hexose Transport
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Xiaoqing Tang, Adilson L Guilherme, Juerg R Straubhaar, Sarah M Nicoloro, Joseph V Virbasius, Abhijit Chakladar, Aimee M Powelka, Silvana Konda, Michael P CzechAbstract:The insulin-regulated glucose Transporter GLUT4 is a key modulator of whole body glucose homeostasis, and its selective loss in adipose tissue or skeletal muscle causes insulin resistance and diabetes. Here we report an RNA interference-based screen of protein kinases expressed in adipocytes and identify four negative regulators of insulin-responsive glucose Transport: the protein kinases PCTAIRE-1 (PCTK1), PFTAIRE-1 (PFTK1), IκB kinase α, and MAP4K4/NIK. Integrin-linked protein kinase was identified as a positive regulator of this process. We characterized one of these hits, MAP4K4/NIK, and found that it is unique among mitogen-activated protein (MAP) kinases expressed in cultured adipocytes in attenuating Hexose Transport. Remarkably, MAP4K4/NIK suppresses expression of the adipogenic transcription factors C/EBPα, C/EBPβ, and PPARγ and of GLUT4 itself in these cells. RNA interference-mediated depletion of MAP4K4/NIK early in differentiation enhances adipogenesis and triglyceride deposition, and even in fully differentiated adipocytes its loss up-regulates GLUT4. Conversely, conditions that inhibit adipogenesis such as TNF-α treatment or depletion of PPARγ markedly up-regulate MAP4K4/NIK expression in cultured adipocytes. Furthermore, TNF-α signaling to down-regulate GLUT4 is impaired in the absence of MAP4K4/NIK, indicating that MAP4K4 expression is required for optimal TNF-α action. These results reveal a MAP4K4/NIK-dependent signaling pathway that potently inhibits PPARγ-responsive gene expression, adipogenesis, and insulin-stimulated glucose Transport.
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insulin signaling through akt protein kinase b analyzed by small interfering rna mediated gene silencing
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Zhen Y Jiang, Qiong L Zhou, Kerri Coleman, My T Chouinard, Queta Boese, Michael P CzechAbstract:Glucose homeostasis is controlled by insulin in part through the translocation of intracellular glucose Transporter 4 to the plasma membrane in muscle and fat cells. Akt/protein kinase B downstream of phosphatidylinositol 3-kinase has been implicated in this insulin-signaling pathway, but results with a variety of reagents including Akt1–/– and Akt2–/– mice have been equivocal. Here we report the application of small interfering RNA-directed gene silencing to deplete both Akt1 and Akt2 in cultured 3T3-L1 adipocytes. Loss of Akt1 alone slightly impaired insulin-mediated Hexose Transport activity but had no detectable effect on glycogen synthase kinase (GSK)-3 phosphorylation. In contrast, depletion of Akt2 alone by 70% inhibited approximately half of the insulin responsiveness. Combined depletions of Akt1 plus Akt2 in these cells even more markedly attenuated insulin action on glucose Transporter 4 movements, Hexose Transport activity, and GSK-3 phosphorylation. These data demonstrate a primary role of Akt2 in insulin signaling, significant functional redundancy of Akt1 and Akt2 isoforms in this pathway, and an absolute requirement of Akt protein kinases for regulation of glucose Transport and GSK-3 in cultured adipocytes.
Peter Rogowsky - One of the best experts on this subject based on the ideXlab platform.
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Seed filling in domesticated maize and rice depends on SWEET-mediated Hexose Transport
Nature Genetics, 2015Co-Authors: Davide Sosso, Dangping Luo, Joelle Sasse, Jinliang Yang, Ghislaine Gendrot, Masaharu Suzuki, Karen E. Koch, Donald R. Mccarty, Prem S. Chourey, Peter RogowskyAbstract:Carbohydrate import into seeds directly determines seed size and must have been increased through domestication. However, evidence of the domestication of sugar translocation and the identities of seed-filling Transporters have been elusive. Maize ZmSWEET4c, as opposed to its sucrose-Transporting homologs, mediates transepithelial Hexose Transport across the basal endosperm transfer layer (BETL), the entry point of nutrients into the seed, and shows signatures indicative of selection during domestication. Mutants of both maize ZmSWEET4c and its rice ortholog OsSWEET4 are defective in seed filling, indicating that a lack of Hexose Transport at the BETL impairs further transfer of sugars imported from the maternal phloem. In both maize and rice, SWEET4 was likely recruited during domestication to enhance sugar import into the endosperm.
Arie Gruzman - One of the best experts on this subject based on the ideXlab platform.
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regulation of glut4 activity in myotubes by 3 o methyl d glucose
Biochimica et Biophysica Acta, 2017Co-Authors: Guy Cohen, Arie Gruzman, Ofer Shamni, Hilal Zaid, Amira Klip, Erol Cerasi, Shlomo SassonAbstract:The rate of glucose influx to skeletal muscles is determined primarily by the number of functional units of glucose Transporter-4 (GLUT4) in the myotube plasma membrane. The abundance of GLUT4 in the plasma membrane is tightly regulated by insulin or contractile activity, which employ distinct pathways to translocate GLUT4-rich vesicles from intracellular compartments. Various studies have indicated that GLUT4 intrinsic activity is also regulated by conformational changes and/or interactions with membrane components and intracellular proteins in the vicinity of the plasma membrane. Here we show that the non-metabolizable glucose analog 3-O-methyl-d-glucose (MeGlc) augmented the rate of Hexose Transport into myotubes by increasing GLUT4 intrinsic activity without altering the content of the Transporter in the plasma membrane. This effect was not a consequence of ATP depletion or hyperosmolar stress and did not involve Akt/PKB or AMPK signal transduction pathways. MeGlc reduced the inhibitory potency (increased Ki) of indinavir, a selective inhibitor of GLUT4, in a dose-dependent manner. Kinetic analyses indicate that MeGlc induced changes in GLUT4 or GLUT4 complexes within the plasma membrane, which enhanced the Hexose Transport activity and reduced the potency of indinavir inhibition. Finally, we present a simple kinetic analysis for screening and discovering low molecular weight compounds that augment GLUT4 activity.
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Supportive data on the regulation of GLUT4 activity by 3-O-methyl-D-glucose
Elsevier, 2017Co-Authors: Ofer Shamni, Guy Cohen, Arie Gruzman, Hilal Zaid, Amira Klip, Erol Cerasi, Shlomo SassonAbstract:The data presented in this article are related to the research article entitled “Regulation of GLUT4 activity in myotubes by 3-O-methyl-D-glucose” (Shamni et al., 2017) [1]. These data show that the experimental procedures used to analyze the effects of 3-O-methyl-D-glucose (MeGlc) on the rate of Hexose Transport into myotubes were valid and controlled. The stimulatory effect of MeGlc was limited to glucose Transporter 4 (GLUT4) and was independent of ambient glucose and protein synthesis. Cornish-Bowden kinetic analysis of uptake data revealed that MeGlc attenuated indinavir-induced inhibition of Hexose Transport in a competitive manner
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adenosine monophosphate activated protein kinase ampk as a new target for antidiabetic drugs a review on metabolic pharmacological and chemical considerations
The review of diabetic studies : RDS, 2009Co-Authors: Arie Gruzman, Gali Babai, Shlomo SassonAbstract:In view of the epidemic nature of type 2 diabetes and the substantial rate of failure of current oral antidiabetic drugs the quest for new therapeutics is intensive. The adenosine monophosphate-activated protein kinase (AMPK) is an important regulatory protein for cellular energy balance and is considered a master switch of glucose and lipid metabolism in various organs, especially in skeletal muscle and liver. In skeletal muscles, AMPK stimulates glucose Transport and fatty acid oxidation. In the liver, it augments fatty acid oxidation and decreases glucose output, cholesterol and triglyceride synthesis. These metabolic effects induced by AMPK are associated with lowering blood glucose levels in hyperglycemic individuals. Two classes of oral antihyperglycemic drugs (biguanidines and thiazolidinediones) have been shown to exert some of their therapeutic effects by directly or indirectly activating AMPK. However, side effects and an acquired resistance to these drugs emphasize the need for the development of novel and efficacious AMPK activators. We have recently discovered a new class of hydrophobic D-xylose derivatives that activates AMPK in skeletal muscles in a non insulin-dependent manner. One of these derivatives (2,4;3,5-dibenzylidene-D-xylose-diethyl-dithioacetal) stimulates the rate of Hexose Transport in skeletal muscle cells by increasing the abundance of glucose Transporter-4 (GLUT-4) in the plasma membrane through activation of AMPK. This compound reduces blood glucose levels in diabetic mice and therefore offers a novel strategy of therapeutic intervention strategy in type 2 diabetes. The present review describes various classes of chemically-related compounds that activate AMPK by direct or indirect interactions and discusses their potential for candidate antihyperglycemic drug development.
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the roles of hyperglycaemia and oxidative stress in the rise and collapse of the natural protective mechanism against vascular endothelial cell dysfunction in diabetes
Archives of Physiology and Biochemistry, 2007Co-Authors: Guy Cohen, Yael Riahi, Evgenia Alpert, Arie Gruzman, Shlomo SassonAbstract:Vascular endothelial cell (VEC) dysfunction in diabetes has been associated with hyperglycaemia-induced intra- and extracellular glycation of proteins and to overproduction of glucose-derived free radicals. VEC protect their intracellular environment against an increased influx of glucose in face of hyperglycaemia by reducing the expression and plasma membrane abundance of their glucose Transporter-1 (GLUT-1). We investigated the hypothesis that glucose-derived free radicals induce this down-regulatory mechanism in VEC, but proved the contrary. In fact, pro-oxidants significantly increased the expression and plasma membrane abundance of GLUT-1 and the rate of glucose Transport in VEC while abolishing high-glucose-induced down-regulation of the Hexose Transport system. The resulting uncontrolled influx of glucose followed by overproduction of glucose-derived ROS further up-regulates the rate of glucose Transport, and vice versa. This perpetuating glycoxidative stress finally leads to the collapse of the auto-regulatory protective mechanism and accelerates the development of dysfunctional endothelium in blood vessels.
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a natural protective mechanism against hyperglycaemia in vascular endothelial and smooth muscle cells role of glucose and 12 hydroxyeicosatetraenoic acid
Biochemical Journal, 2002Co-Authors: Evgenia Alpert, Arie Gruzman, Hanan Totary, Nurit Kaiser, Reuven Reich, Shlomo SassonAbstract:Bovine aortic endothelial and smooth-muscle cells down-regulate the rate of glucose Transport in the face of hyperglycaemia, thus providing protection against deleterious effects of increased intracellular glucose levels. When exposed to high glucose concentrations these cells reduced the mRNA and protein content of their typical glucose Transporter, GLUT-1, as well as its plasma-membrane abundance. Inhibition of the lipoxygenase (LO) pathway, and particularly 12-LO, reversed this glucose-induced down-regulatory process and restored the rate of Hexose Transport to the level seen in vascular cells exposed to normal glucose levels. This reversal was accompanied by increased levels of GLUT-1 mRNA and protein, as well as of its plasma-membrane content. Exposure of the vascular cells to elevated glucose concentrations increased by 2-3-fold the levels of cell-associated and secreted 12-hydroxyeicosatetraenoic acid (12-HETE), the product of 12-LO. Inhibition of 15- and 5-LO, cyclo-oxygenases 1 and 2, and eicosanoid-producing cytochrome P450 did not modify the Hexose-Transport system in vascular cells. These results suggest a role for HETEs in the autoregulation of Hexose Transport in vascular cells. 8-Iso prostaglandin F(2alpha), a non-enzymic oxidation product of arachidonic acid, had no effect on the Hexose-Transport system in vascular cells exposed to hyperglycaemic conditions. Taken together, these findings show that hyperglycaemia increases the production rate of 12-HETE, which in turn mediates the down-regulation of GLUT-1 expression and the glucose-Transport system in vascular endothelial and smooth-muscle cells.
Eckhard Boles - One of the best experts on this subject based on the ideXlab platform.
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role of Hexose Transport in control of glycolytic flux in saccharomyces cerevisiae
Applied and Environmental Microbiology, 2004Co-Authors: Karin Elbing, Eckhard Boles, Christer Larsson, Roslyn M Bill, Eva Albers, Jacky L Snoep, Stefan Hohmann, Lena GustafssonAbstract:The yeast Saccharomyces cerevisiae predominantly ferments glucose to ethanol at high external glucose concentrations, irrespective of the presence of oxygen. In contrast, at low external glucose concentrations and in the presence of oxygen, as in a glucose-limited chemostat, no ethanol is produced. The importance of the external glucose concentration suggests a central role for the affinity and maximal Transport rates of yeast’s glucose Transporters in the control of ethanol production. Here we present a series of strains producing functional chimeras between the Hexose Transporters Hxt1 and Hxt7, each of which has distinct glucose Transport characteristics. The strains display a range of decreasing glycolytic rates resulting in a proportional decrease in ethanol production. Using these strains, we show for the first time that at high glucose levels, the glucose uptake capacity of wild-type S. cerevisiae does not control glycolytic flux during exponential batch growth. In contrast, our chimeric Hxt Transporters control the rate of glycolysis to a high degree. Strains whose glucose uptake is mediated by these chimeric Transporters will undoubtedly provide a powerful tool with which to examine in detail the mechanism underlying the switch between fermentation and respiration in S. cerevisiae and will provide new tools for the control of industrial fermentations. The ability of the yeast Saccharomyces cerevisiae to readily degrade sugars to ethanol and carbon dioxide (CO2) has been utilized by humans for several thousands of years for the fermentation of alcoholic beverages and bread baking. S. cerevisiae ferments sugars even under aerobic conditions when the glucose concentration in the medium exceeds 0.8 mM (15, 48). This causes diauxic growth in aerobic batch cultures: once glucose is consumed, the ethanol is oxidized to CO2 in a second, strictly respiratory growth phase. In contrast, at low ex
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arsenic trioxide uptake by Hexose permeases in saccharomyces cerevisiae
Journal of Biological Chemistry, 2004Co-Authors: Zijuan Liu, Eckhard Boles, Barry P. RosenAbstract:Arsenic trioxide is a toxic metalloid and carcinogen that is also used as an anticancer drug, and for this reason it is important to identify the routes of arsenite uptake by cells. In this study the ability of Hexose Transporters to facilitate arsenic trioxide uptake in Saccharomyces cerevisiae was examined. In the absence of glucose, strains with disruption of the arsenite efflux gene ACR3 accumulated high levels of (73)As(OH)(3). The addition of glucose inhibited uptake by approximately 80%. Disruption of FPS1, the aquaglyceroporin gene, reduced glucose-independent uptake by only about 25%, and the residual uptake was nearly completely inhibited by Hexoses, including glucose, galactose, mannose, and fructose but not pentoses or disaccharides. A strain lacking FPS1, ACR3, and all genes for Hexose permeases except for HXT3, HXT6, HXT7, and GAL2 exhibited Hexose-inhibitable (73)As(OH)(3) uptake, whereas a strain lacking all 18 Hexose Transport-related genes (HXT1 to HXT17 and GAL2), FPS1 and ACR3, exhibited <10% of wild type (73)As(OH)(3) Transport. When HXT1, HXT3, HXT4, HXT5, HXT7, or HXT9 was individually expressed in that strain, Hexose-inhibitable (73)As(OH)(3) uptake was restored. In addition, the Transport of [(14)C]glucose was inhibited by As(OH)(3). These results clearly demonstrate that Hexose permeases catalyze the majority of the Transport of the trivalent metalloid arsenic trioxide.
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kinetic characterization of individual Hexose Transporters of saccharomyces cerevisiae and their relation to the triggering mechanisms of glucose repression
FEBS Journal, 1997Co-Authors: Elke Reifenberger, Eckhard Boles, Michael CiriacyAbstract:In Saccharomyces cerevisiae, there are a large number of genes (HXT1-HXT17/SNF3/RGT2) encoding putative Hexose Transporters which, together with a galactose permease gene (GAL2), belong to a superfamily of monosaccharide facilitator genes. We have performed a systematic analysis of the HXT1–7 and GAL2 genes and their function in Hexose Transport. Glucose uptake was below the detection level in the hxt1–7 null strain growing on maltose. Determination of the kinetic parameters of individual Hexose Transporter-related proteins (Hxtp) expressed in the hxt null background revealed Hxt1p and Hxt3p as low-affinity Transporters (Km(glucose)= 50–100mM), Hxt2p and Hxt4p as moderately low in affinity (Km(glucose) about 10 mM), and Hxt6p, Hxt7p as well as Gal2p as high-affinity Transporters (Km(glucose)= 1–2 mM). However, Hxt2p kinetics in cells grown on low glucose concentrations showed a high-affinity (Km =1.5 mM) and a low-affinity component (Km= 60 mM). Furthermore, we investigated the involvement of glucose Transport in glucose signalling. Glucose repression of MAL2, SUC2 and GAL1 was not dependent on a specific Transporter but, instead, the strength of the repression signal was dependent on the level of expression, the properties of the individual Transporters and the kind of sugar Transported. The strength of the glucose repression signal correlated with the glucose consumption rates in the different strains, indicating that glucose Transport limits the provision of a triggering signal rather then being directly involved in the triggering mechanism.