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Results for “Signal Transduction”

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PubMed1995

Model for external influences on cellular signal transduction pathways including cytosolic calcium oscillations.

Experiments on the effects of extremely-low-frequency (ELF) electric and magnetic fields on cells of the immune system, T-lymphocytes in particular, suggest that the external field interacts with the cell at the level of intracellular signal transduction pathways. These are directly connected with changes in the calcium-signaling processes of the cell. Based on these findings, a theoretical model for receptor-controlled cytosolic calcium oscillations and for external influences on the signal transduction pathway is presented. We discuss the possibility that the external field acts on the kinetics of the signal transduction between the activated receptors at the cell membrane and the G-proteins. It is shown that, depending on the specific combination of cell internal biochemical and external physical parameters, entirely different responses of the cell can occur. We compare the effects of a coherent (periodic) modulation and of incoherent perturbations (noise). The model and the calculations are based on the theory of self-sustained, nonlinear oscillators. It is argued that these systems form an ideal basis for information-encoding processes in biological systems.

Algorithms↗

PubMed2003

The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and proliferation.

Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK). FRK/RAK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where they both induce PC12 cell differentiation and beta-cell proliferation. Furthermore, beta-cell apoptosis is augmented by these proteins under conditions that cause beta-cell degeneration. The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2. Besides regulating apoptosis, proliferation and differentiation, SHB is also a component of the T cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production. In endothelial cells, SHB both promotes apoptosis under conditions that are anti-angiogenic, but is also required for proper mitogenicity, spreading and tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K) prevents early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon, suggesting a role of SHB in development. In summary, SHB is a versatile signal transduction molecule that produces diverse biological responses in different cell types under various conditions. SHB operates downstream of GTK in cells that express this kinase.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Elicitor signal transduction leading to production of plant secondary metabolites.

Plant secondary metabolites are unique sources for pharmaceuticals, food additives, flavors, and other industrial materials. Accumulation of such metabolites often occurs in plants subjected to stresses including various elicitors or signal molecules. Understanding signal transduction paths underlying elicitor-induced production of secondary metabolites is important for optimizing their commercial production. This paper summarizes progress made on several aspects of elicitor signal transduction leading to production of plant secondary metabolites, including: elicitor signal perception by various receptors of plants; avirulence determinants and corresponding plant R proteins; heterotrimeric and small GTP binding proteins; ion fluxes, especially Ca2+ influx, and Ca2+ signaling; medium alkalinization and cytoplasmic acidification; oxidative burst and reactive oxygen species; inositol trisphosphates and cyclic nucleotides (cAMP and cGMP); salicylic acid and nitric oxide; jasmonate, ethylene, and abscisic acid signaling; oxylipin signals such as allene oxide synthase-dependent jasmonate and hydroperoxide lyase-dependent C12 and C6 volatiles; as well as other lipid messengers such as lysophosphatidylcholine, phosphatidic acid, and diacylglycerol. All these signal components are employed directly or indirectly by elicitors for induction of plant secondary metabolite accumulation. Cross-talk between different signaling pathways is very common in plant defense response, thus the cross-talk amongst these signaling pathways, such as elicitor and jasmonate, jasmonate and ethylene, and each of these with reactive oxygen species, is discussed separately. This review also highlights the integration of multiple signaling pathways into or by transcription factors, as well as the linkage of the above signal components in elicitor signaling network through protein phosphorylation and dephosphorylation. Some perspectives on elicitor signal transduction and plant secondary metabolism at the transcriptome and metabolome levels are also presented.

Gene Expression Regulation, Plant↗

PubMed1995

Multiphasic modulation of signal transduction into T lymphocytes by monoiodoacetic acid as a sulfhydryl reagent.

Actions of monoiodoacetic acid (MIA) as a sulfhydryl reagent on the different stages of the T cell receptor (TCR)-mediated signal transduction were examined. MIA (1 mM) prevented anti-TCR (CD3) monoclonal antibody (mAb)-induced energy-dependent receptor capping but at the same time promoted the anti-CD3 mAb/mitogen-induced tyrosine phosphorylation of the T cell activation-linked cellular proteins of 120, 80, 70, 56, and 40 kDa. Relatively low concentration (0.01 mM) of MIA further promoted anti-CD3 mAb-induced transcription of c-fos, production of IL-2, and cell surface expression of IL-2 receptors. The MIA-promoted TCR-mediated IL-2 production actually required signal transduction that could be inhibited by cyclosporin A, genistein, or H-7. In contrast, the same concentration of MIA as promoted the signal transduction for cell activation severely inhibited the anti-CD3 mAb-triggered signal delivery for cell proliferation, selectively at its early stage. We conclude from these results that MIA differentially affects various steps of signaling into T lymphocytes, suggesting that there exist multiple sites of MIA-sensitive or redox-linked control in the signal cascade.

Animals↗

PubMed1994

A new system that analyzes erythropoietin-mediated early signal transduction: transfection of the c-fos enhancer.promoter-luciferase gene into a murine erythroid cell line.

Erythropoietin (Epo) exerts its effects by binding specific receptors on the surface of reactive cells. However, the signal transduction system after binding has not been well described. To develop a system to analyze the steps of signal transduction, we transfected the human c-fos-enhancer/promoter linked with the Photinus pyralis luciferase gene (pfosluc2) into a murine erythroleukemia cell line ELM-I-1, in which we previously showed that c-fos mRNA is rapidly induced upon Epo-stimulation. A stable transfectant was obtained. The cells transfected with pfosluc2 were stimulated with Epo and luciferase activity in the cells was measured as light intensity. The light intensity integrated for 2 min (LI2.0) was 3202 +/- 80 unit/1.5 x 10(5) cells before stimulation. This increased up to 5869 +/- 321 unit/1.5 x 10(5) cells by incubating the cells with 5 U/ml Epo for 2 h. After Epo stimulation, light intensity began to increase at 30 min, reached a peak (about 1.8 times the basal level) at 120 min, and then gradually dropped. The effect of Epo was dose-dependent; significant action occurred at as low as 0.5 U/ml, with a maximum at 5 U/ml. A similar response was observed when the cells were stimulated with interleukin-3 (IL-3) although the response was apparently lower than that with Epo. It was also found that IL-3 had an additive action with Epo on c-fos activity in this system. Thus, the above method was proven to be simple, rapid and sensitive enough to use to determine the early phase of signal transduction of Epo.

Animals↗

PubMed1999

Protein kinase C in the treatment of disease: signal transduction pathways, inhibitors, and agents in development.

Protein kinase C (PKC) is a family of enzymes that play a ubiquitous role in intracellular signal transduction. Our understanding of the precise role of PKC has evolved considerably as a result of improved methodology and a better understanding of the signal transduction pathways. A number of primary pathways previously attributed to PKC have been re-examined and found to involve other kinases as our understanding of the PKC isozymes has evolved. PKC isozymes appear to play distinct, and in some cases opposing roles in the transduction of intracellular signals. The development of potent and selective PKC inhibitors, including isozyme-selective inhibitors, has opened new avenues for biochemical and pharmaceutical studies. The role of PKC in some of the pathways relevant to cardiovascular, peripheral microvascular, CNS, oncology, immune and infectious disease states are surveyed. A survey of the current generation of potent and selective ATP-competitive inhibitors is provided. The progress of PKC inhibitors currently in clinical development, including LY333531, ISIS 3521 (CGP 64128A), bryostatin 1, GF109203x, Ro 32-0432 and Ro 31-8220, Go 6976 and Go 7611, CPR 1006, and balanol (SPC 100840) are discussed.

Azepines↗

PubMed1995

Signal transduction by the hepatocyte growth factor receptor, c-met. Activation of the phosphatidylinositol 3-kinase.

Signal transduction by tyrosine kinase growth factor receptors involves the activation of multiple intracellular signaling pathways. In many cases, this occurs via direct binding of a downstream signaling protein to the phosphorylated receptor via src-homology 2 domains on the signaling protein. In this review of the hepatocyte growth factor receptor c-met, the ability of the amino acid sequence of the receptor to dictate which signaling proteins are activated is described, with particular emphasis on association with the phosphatidylinositol 3-kinase. Recent developments that provide new understanding of the mechanisms of downstream signal transduction by the phosphatidylinositol 3-kinase are discussed, including how these might be involved in the mitogenic, motogenic, and tubulogenic effects of hepatocyte growth factor on renal epithelial cells.

Amino Acid Sequence↗

PubMed2003

Effects of lentinan on broiler splenocyte proliferation, interleukin-2 production, and signal transduction.

Lentinan (LEN) is an intensively studied beta-glucan that has been shown to have immunostimulating and antitumor functions. However, it currently is not used in veterinary practice and animal production. This study was conducted to investigate the impacts of LEN on broiler splenocyte proliferation, interleukin-2 (IL-2) production, and to explore its effects on receptor signal transduction by determining signaling molecules, including nitric oxide (NO), cytosolic-free Ca2+, cytosolic cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP). The results showed that compared to the control all three measured doses, including 40, 80, and 160 microg/mL LEN, increased splenocyte proliferation and IL-2 production (P < 0.05). Lentinan increased splenocyte NO production and cytosolic-free calcium concentration in a dose-dependent manner (P < 0.001). After incubating splenocytes for 20 min, LEN increased intracellular cAMP and cGMP concentrations at a dose of 80 and 160 microg/mL, respectively. However, after incubating the splenocytes for 60 min, LEN had no effect on cytosolic cAMP and cGMP concentration irrespective of the LEN dosage. Those results indicated that LEN had immunostimulatory effects on splenocytes by increasing splenocyte proliferation and IL-2 production and by activating splenocyte receptor signal transduction.

Adjuvants, Immunologic↗

PubMed1997

Evidence supporting a signal transduction pathway leading to the radiation-resistant phenotype in human tumor cells.

A signal transduction pathway, involving oncogenes and their normal counterparts the proto-oncogenes, analogous to that for cell growth and differentiation has been proposed to lead to the phenotype of cellular radioresistance (RR). In this report we provide evidence demonstrating the existence of such a pathway by using antisense oligonucleotides (ASO) to reverse the RR phenotype. Utilizing ASO directed against the raf-1 gene, a central component of this proposed pathway, we were able to reverse the RR phenotype of human tumor cell lines having elevated HER-2 expression or a mutant form of Ha-ras, two genes upstream of raf-1 in signal transduction. Additionally, anti-ras ASO were able to radiosensitize HER-2 overexpressing cells. These results, which verify the presence of a signaling pathway leading to cellular RR, also have possible clinical implications for the use of ASO as a means to sensitize radioresistant tumors to radiation therapy.

Breast↗

PubMed1989

Membrane signal transduction in T cells in aging humans.

The interaction of the T cell receptor complex with the ligand is associated with early molecular events involved in the process of signal transduction. These events include, changes in membrane potentials, intracellular free calcium [(Ca++)i], and the activation and translocation of protein kinase C (PKC). The aim of this study was to elucidate the abnormalities in membrane signal transduction pathway as the basis of T cell-mediated immune deficiency associated with aging. Peripheral blood mononuclear cells from aging humans and sex-matched young subjects were stimulated with anti-CD3 monoclonal antibody, WT31 monoclonal antibody (defines epitopes for alpha/beta T cell receptor genes), and phytohemagglutinin (PHA), and examined for the changes in plasma membrane potentials, changes in (Ca++)i, and the activation of PKC. The membrane potentials were measured with DiOC5 dye using FACS. Intracellular free calcium was measured with quin-2 dye and spectrofluorimeter, and the membrane and cytosolic PKC were measured by an enzyme assay. The resting membrane potentials in aging T cells were decreased (plasma membrane depolarized) when compared to T cells from young subjects. In T cells from aging humans, there was a lack of a change in the membrane potentials or membrane potentials were increased (plasma membrane hyperpolarized) following activation with anti-CD3 and WT31 monoclonal antibodies, whereas in young T cells membrane potentials were decreased (depolarized). The basal [Ca++]i levels in aging T cells were less than that in young T cells, and a much smaller rise in [Ca++]i was observed following activation with PHA and anti-CD3 monoclonal antibody in aging T cells than in the young T cells. In aging cells there was less translocation of PKC from cytosol to the membrane following activation with anti-CD3 and WT31. This study demonstrates that the abnormal membrane signal transduction pathway plays a role in T cell dysfunctions associated with human aging.

Adult↗

PubMed1997

In vitro phosphorylation study of the arc two-component signal transduction system of Escherichia coli.

The ArcB and ArcA proteins constitute a two-component signal transduction system that plays a broad role in transcriptional regulation. Under anoxic or environmentally reducing conditions, the sensor kinase (ArcB) is stimulated to autophosphorylate at the expense of ATP and subsequently transphosphorylates the response regulator (ArcA). ArcB is a complex, membrane-bound protein comprising at least three cytoplasmic domains, an N-terminal transmitter domain with a conserved His292 residue (H1), a central receiver domain with a conserved Asp576 residue (D1), and a C-terminal alternative transmitter domain with a conserved His717 residue (H2). To study the phosphoryl transfer pathways of the Arc system, we prepared the following His-tagged proteins: H1, D1, H2, H1-D1, D1-H2, H1-D1-H2, and ArcA. Incubations of various combinations of Arc proteins with [gamma-32P]ATP indicated that H1, but not D1 or H2, catalyzes autophosphorylation; that H1-P transfers the phosphoryl group to D1 much more rapidly than to ArcA; and that D1 accelerates the transphosphorylation of H2. Finally, ArcA is phosphorylated much more rapidly by H2-P than by H1-P. Available data are consistent with a signal transduction model in which (i) reception of a membrane signal(s) triggers autophosphorylation of H1 at His292, (ii) the phosphoryl group can migrate to D1 at Asp576 and subsequently to H2 at His717, and (iii) ArcA receives the phosphoryl group from either His292 or His717, the relative contribution of which is regulated by cytosolic effectors.

Bacterial Outer Membrane Proteins↗

PubMed1994

Regulation of Sertoli cell differentiation by the testicular paracrine factor PModS: analysis of common signal transduction pathways.

In the testis the mesenchymally derived peritubular cells produce a paracrine factor, PModS, that mediates mesenchymal-epithelial interactions and modulates Sertoli cell functions essential for the process of spermatogenesis. PModS has a more dramatic effect on Sertoli cell differentiated functions in vitro than any regulatory agent previously shown to influence the cells, including FSH. The current study initiates an investigation of the pharmacology of PModS through an analysis of several common signal transduction pathways. PModS was found to stimulate cGMP levels in Sertoli cells and maintain elevated levels for up to 5 days in culture. PModS had no influence on cAMP levels. In contrast, FSH stimulated cAMP, but had no influence on cGMP levels. For comparison, an agent known to influence cGMP levels, atrial naturetic factor (ANF), was used to treat Sertoli cells. ANF caused a dramatic increase in Sertoli cell cGMP levels within minutes of treatment, but did not maintain elevated cGMP levels after a 72-h treatment. Although ANF increased guanylate cyclase in whole Sertoli cell homogenates and particulate fractions, PModS did not directly influence guanylate cyclase activity. As previously shown, PModS stimulates transferrin expression as a marker of Sertoli cell differentiated function. Agents that elevate cellular cGMP, including ANF, sodium nitroprusside, and 8-bromo-cGMP, did not influence Sertoli cell transferrin expression. In addition, these agents did not influence the actions of PModS or FSH. Therefore, cGMP does not appear to directly mediate the actions of PModS. As an alternative signal transduction pathway, calcium mobilization and inositol phosphate (IP) metabolism were examined. PModS did not alter calcium uptake or intracellular calcium mobilization. PModS also did not influence the levels of inositol mono-, bis-, or trisphosphates, whereas calf serum did stimulate levels of all three IP metabolites in Sertoli cells. Therefore, PModS does not appear to act through a mobilization of calcium or increased metabolism of IP. A final signal transduction pathway involving phosphorylation was also examined. PModS treatment was found to increase tyrosine phosphorylation of specific proteins in a crude Sertoli cell cytosol preparation. Genistein is an inhibitor of tyrosine kinases and was found to reduce PModS actions at a 3.7-microM concentration of genistein and inhibit PModS actions at a 37-microM concentration of genistein. Therefore, PModS may act through a tyrosine phosphorylation event that remains to be elucidated. Combined observations indicate that PModS does not use cyclic nucleotides, calcium mobilization, or IP metabolism as a signal transduction pathway.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2003

A possible mechanism for improvement by a cognition-enhancer nefiracetam of spatial memory function and cAMP-mediated signal transduction system in sustained cerebral ischaemia in rats.

1. Accumulated evidence indicates that the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signal transduction system may be linked to learning and memory function. 2. The effects of nefiracetam, which has been developed as a cognition enhancer, on spatial memory function and the AC/cAMP/PKA/CREB signal transduction system in rats with sustained cerebral ischaemia were examined. 3. Microsphere embolism (ME)-induced sustained cerebral ischaemia was produced by injection of 700 microspheres (48 micro m in diameter) into the right hemisphere of rats. Daily oral administration of nefiracetam (10 mg kg(-1) day(-1)) was started from 15 h after the operation. 4. The delayed treatment with nefiracetam attenuated the ME-induced prolongation of the escape latency in the water maze task that was examined on day 7 to 9 after ME, but it did not reduce the infarct size. 5. ME decreased Ca(2+)/calmodulin (CaM)-stimulated AC (AC-I) activity, cAMP content, cytosolic PKA Cbeta level, nuclear PKA Calpha and Cbeta levels, and reduced the phosphorylation and DNA-binding activity of CREB in the nucleus in the right parietal cortex and hippocampus on day 3 after ME. The ME-induced changes in these variables did not occur by the delayed treatment with nefiracetam. 6. These results suggest that nefiracetam preserved cognitive function, or prevented cognitive dysfunction, after sustained cerebral ischaemia and that the effect is, in part, attributable to the prevention of the ischaemia-induced impairment of the AC/cAMP/PKA/CREB signal transduction pathway.

Animals↗

PubMed1993

Glucose-induced insulin secretion from purified beta-cells. A role for modulation of Ca2+ influx by cAMP- and protein kinase C-dependent signal transduction pathways.

The effects of activation of cAMP- and protein kinase C-dependent signal transduction pathways were investigated on intracellular Ca2+ concentration ([Ca2+]i), cAMP content and insulin secretion from beta-cells purified by fluorescence-activated cell sorting from normal rat islets. The secretion of insulin from suspensions of purified beta-cells was dependent on glucose concentration and hormonal signals, including cAMP and activators of protein kinase C. Microfluorimetric measurement of [Ca2+]i with the fluorescent Ca2+ indicator fura-2 indicated that beta-cells differed immensely in their individual responsiveness to glucose stimulation. An increase in [Ca2+]i occurred in approximately 70% of beta-cells, whereas approximately 30% of beta-cells were nonresponsive to a glucose stimulus. Elevation of cAMP levels by theophylline or glucagon transformed nonresponsive beta-cells into cells which displayed marked increases in [Ca2+]i, and beta-cells which exhibited glucose-induced changes in [Ca2+]i showed further increases in [Ca2+]i and in the amplitude of Ca2+ oscillations. Carbachol and 12-O-tetradecanoylphorbol-13-acetate, activators of protein kinase C, did not induce any alterations in intracellular cAMP levels; nonetheless, these agents increased both the number of beta-cells which exhibited glucose-induced changes in [Ca2+]i and the amplitude of oscillations. The ability of cAMP or activators of protein kinase C to increase [Ca2+]i in single beta-cells was directly correlated with the ability of beta-cell suspensions to secrete insulin in response to a glucose stimulus. These results suggest that both cAMP- and protein kinase C-dependent pathways may regulate Ca2+ entry into beta-cells, possibly via voltage-dependent Ca2+ channels. Thus, this may represent a common mechanism whereby these different signal transduction pathways potentiate glucose-induced insulin secretion from beta-cells.

Animals↗

PubMed2004

Tissue factor as an evolutionary conserved cytokine receptor: Implications for inflammation and signal transduction.

Tissue factor (TF) is a transmembrane protein that, in complex with factor VIIa (FVIIa), initiates coagulation. It also influences various other physiological and pathological events, such as inflammation, and negatively influences survival during sepsis. TF resembles a conserved class of pro-inflammatory cytokine receptors and activates a set of pro-inflammatory intracellular signal transduction routes. Interestingly, whereas the homology of TF to the class II cytokine receptors is reflected in a similar type of signal transduction, the mechanism by which the signal is transduced across the membrane differs greatly. This review discusses the role of TF and its ligand FVIIa in inflammation, sepsis, and signal transduction, and describes the way in which these processes interact.

Animals↗

PubMed1999

Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats.

To determine whether defects in the insulin signal transduction pathway to glucose transport occur in a muscle fiber type-specific manner, post-receptor insulin-signaling events were assessed in oxidative (soleus) and glycolytic (extensor digitorum longus [EDL]) skeletal muscle from Wistar or diabetic GK rats. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) glucose transport was significantly decreased, compared with that of Wistar rats. In EDL muscle from GK rats, maximal insulin-stimulated glucose transport was normal, while the submaximal response was reduced compared with that of Wistar rats. We next treated diabetic GK rats with phlorizin for 4 weeks to determine whether restoration of glycemia would lead to improved insulin signal transduction. Phlorizin treatment of GK rats resulted in full restoration of insulin-stimulated glucose transport in soleus and EDL muscle. In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. In EDL muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and Wistar rats. Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). Here, we show that in EDL muscle from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment. In conclusion, functional defects in IRS-1 and PI 3-kinase in skeletal muscle from diabetic GK rats are fiber-type-specific, with alterations observed in oxidative, but not glycolytic, muscle. Furthermore, regardless of muscle fiber type, downstream steps to PI 3-kinase (i.e., Akt and glucose transport) are sensitive to changes in the level of glycemia.

3-O-Methylglucose↗

PubMed2005

PII signal transduction proteins: sensors of alpha-ketoglutarate that regulate nitrogen metabolism.

PII proteins are small homotrimeric signal transduction proteins that regulate the activities of metabolic enzymes and permeases, and control the activities of signal transduction enzymes. The protein family shows high conservation, with examples in eukaryota (plants and eukaryotic algae), archaea, and bacteria. This distribution indicates that PII is one of the most ancient signalling proteins known.

Bacterial Physiological Phenomena↗

PubMed2001

Age-related alterations in the signal transduction pathways of the elastin-laminin receptor.

With aging we assist to alterations in the vascular structure and function. One important factor in these vascular wall changes is the degradation of the elastin fibre major protein: elastin. Elastin peptides derived from the degradation are present in human sera. Elastin peptides induce on fibroblasts, phagocytic cells, lymphocytes, smooth muscle cells and endothelial cells, a variety of biological effects mediated by the elastin-laminin receptor which has been demonstrated to be present on the membrane of these cells. The transduction pathway of the ELR receptor involves the activation of phospholipase C (PLC) by a pertussis toxin sensitive G-protein. PLC induces the production of inositol trisphosphate (IP3) leading to the increase of the intracellular free calcium on one hand, and of diacylglycerol (DAG) which stimulates the translocation to the membrane of PKC leading to the phosphorylation of members of the MAPK family, such as p42/p44 MAPK. A progressive age dependent uncoupling of the elastin-laminin receptor occurs impairing its transduction pathway and which results in alteration of the calcium signaling and loss in calcium homeostasis of the cells. These alterations in the signal transduction of the elastin-laminin receptor result in modified activities of parenchymal and phagocytic cells with aging, such as free radical production and elastase release. Thus, these age-related alterations in the elastin-laminin receptor signal transduction may be involved in the atherogenesis.

Aging↗