Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Presynaptic inhibition of transmitter release is commonly mediated by a direct interaction between G protein betagamma subunits and voltage-activated Ca2+ channels. To search for an alternative pathway, the mechanisms by which presynaptic bradykinin receptors mediate an inhibition of noradrenaline release from rat superior cervical ganglion neurons were investigated. The peptide reduced noradrenaline release triggered by K+-depolarization but not that evoked by ATP, with Ca2+ channels being blocked by Cd2+. Bradykinin also reduced Ca2+ current amplitudes measured at neuronal somata, and this effect was pertussis toxin-insensitive, voltage-independent, and developed slowly within 1 min. The inhibition of Ca2+ currents was abolished by a phospholipase C inhibitor, but it was not altered by a phospholipase A2 inhibitor, by the depletion of intracellular Ca2+ stores, or by the inactivation of protein kinase C or Rho proteins. In whole-cell recordings, the reduction of Ca2+ currents was irreversible but became reversible when 4 mM ATP or 0.2 mM dioctanoyl phosphatidylinositol-4,5-bisphosphate was included in the pipette solution. In contrast, the effect of bradykinin was entirely reversible in perforated-patch recordings but became irreversible when the resynthesis of phosphatidylinositol-4,5-bisphosphate was blocked. Thus, the inhibition of Ca2+ currents by bradykinin involved a consumption of phosphatidylinositol-4,5-bisphosphate by phospholipase C but no downstream effectors of this enzyme. The reduction of noradrenaline release by bradykinin was also abolished by the inhibition of phospholipase C or of the resynthesis of phosphatidylinositol-4,5-bisphosphate. These results show that the presynaptic inhibition was mediated by a closure of voltage-gated Ca2+ channels through depletion of membrane phosphatidylinositol bisphosphates via phospholipase C.
...
PMID:Presynaptic inhibition via a phospholipase C- and phosphatidylinositol bisphosphate-dependent regulation of neuronal Ca2+ channels. 1609 42

The effects of bradykinin on nicotine-induced responses were investigated in neurons dissociated from rat paratracheal ganglia using the nystatin-perforated patch-clamp recording technique. When bradykinin (10(-9) to 10(-8) M) was pretreated and then simultaneously applied with 10(-5) M nicotine, bradykinin potentiated the nicotine-induced currents. The potentiation was mimicked by [Hyp3]-bradykinin and inhibited by HOE-140, pertussis toxin, neomycin and U-73122, but not U-73433. These results suggest that bradykinin potentiates nicotinic currents via bradykinin B2 receptor, pertussis toxin-sensitive G-protein and phospholipase C. Since bradykinin inhibits the M-current via bradykinin B2 receptor and pertussis toxin-insensitive G-protein [Mochidome, T., Ishibashi, H., Takahama, K., 2001. Bradykinin activates airway parasympathetic ganglion neurons by inhibiting M-currents. Neuroscience 105, 785-791.], it seemed that bradykinin B2 receptor activated two distinct signal transduction pathways in the paratracheal ganglia neurons. This effect of bradykinin might cause enhanced synaptic transmission in paratracheal ganglia neurons and contribute to the aggravation of pathological conditions of the lower airway via enhanced acetylcholine release from the postganglionic nerve terminals.
...
PMID:Potentiation of nicotinic currents by bradykinin in the paratracheal ganglia neurons of rats. 1644 93

Bradykinin is a potent vasoactive nonapeptide. It elicits a rise in cytosolic Ca(2+) (Ca(2+))(i) in endothelial cells, resulting in Ca(2+)-dependent synthesis and release of endothelial vasodilators. In the present study, we investigated the mechanism of bradykinin-induced Ca(2+) influx in primary cultured rat aortic endothelial cells and in a mouse heart microvessel endothelial cell line (H5V). Bradykinin-induced Ca(2+) influx was resolved into capacitative Ca(2+) entry (CCE) and non-CCE. The non-CCE component was inhibited by a B2 receptor antagonist (HOE140; 1 microM) and a phospholipase C (PLC) inhibitor (U73122; 10 microM). The action of bradykinin could be mimicked by 1-oleoyl-2-acetyl-glycerol, an analogue of diacylglycerol (DAG), and by RHC80267, a DAG-lipase inhibitor. Immunoblots showed that TRPC6 was one of the main TRPC channels expressed in endothelial cells. Transfection of H5V cells with two siRNA constructs against TRPC6 both markedly reduced the TRPC6 protein level and, at the same time, decreased the percentage of cells displaying bradykinin-induced non-CCE. siRNA transfection also reduced the magnitude of non-CCE among the cells responding to bradykinin. Taken together, our data suggest that bradykinin-induced non-CCE is mediated via the B2-PLC pathway, and that DAG may be involved in this process. Further, TRPC6 is one of the important channels participating in bradykinin-induced non-CCE in endothelial cells.
...
PMID:Mechanism of non-capacitative Ca2+ influx in response to bradykinin in vascular endothelial cells. 1679 Oct 8

Bradykinin produced at sites of tissue injury and inflammation elicits acute pain and alters the sensitivity of nociceptive neurons to subsequent stimuli. We tested the hypothesis that bradykinin could elicit long-lasting changes in nociceptor function by activating members of the nuclear factor of activated T-cells (NFAT) family of transcription factors. Bradykinin activation of B2 receptors evoked concentration-dependent (EC50 = 6.0 +/- 0.3 nM) increases in intracellular Ca2+ concentration ([Ca2+]i) in a proportion of dorsal root ganglion neurons in primary culture. These [Ca2+] increases were sensitive to inhibition of phospholipase C (PLC) and depletion of Ca2+ stores. In neurons expressing a green fluorescent protein (GFP)-NFAT4 fusion protein, a 2-min exposure to bradykinin induced the translocation of GFP-NFAT4 from the cytoplasm to the nucleus. Translocation was partially inhibited by the removal of extracellular Ca2+ and was blocked by inhibition of calcineurin. Furthermore, bradykinin triggered a concentration-dependent increase in NFAT-mediated transcription of a luciferase gene reporter (EC50 = 24.2 +/- 0.1 nM). This depended on the B2 receptor, PLC activation, and inositol triphosphate-mediated Ca2+ release. Transcription was not inhibited by capsazepine. Finally, as indicated by quantitative reverse transcription-polymerase chain reaction, bradykinin elicited an increase in cyclooxygenase mRNA. This increase was sensitive to calcineurin and B2 receptor inhibition. These findings suggest a mechanism by which short-lived bradykinin-mediated stimuli can enact lasting changes in nociceptor function and sensitivity.
...
PMID:Bradykinin-induced nuclear factor of activated T-cells-dependent transcription in rat dorsal root ganglion neurons. 1748 65

This study aimed to study the effect of bradykinin on reactive oxygen species (ROS) generation, mitochondrial injury, and cell death induced by ATP depletion in cell culture. Renal tubular cells were subjected to ATP depletion. Cell death was evaluated with LDH release, sub-G0/G1 fraction, Hoechst staining, and annexin V binding assay. ROS generation, mitochondrial membrane potential (DeltaPsi(m)), and intramitochondrial calcium were evaluated with flow cytometry. Translocation of cytochrome c and activation of apoptotic protein were analyzed with cell fractionating and Western blotting. Intracellular calcium was measured with a spectrofluorometer. Bradykinin enhanced cellular LDH release, apoptosis, generation of superoxide, and hydrogen peroxide induced by ATP depletion. Bradykinin also enhanced the loss of DeltaPsi(m), translocation of cytochrome c into cytosol, and activation of apoptotic protein. The intracellular/mitochondrial calcium was higher in bradykinin-treated cells. All these effects were reversed by coadministration with bradykinin B2 receptor (B2R) antagonist. Besides, blocking the phospholipase C (PLC) could reverse the synergistic effect of bradykinin with ATP depletion on ROS generation, mitochondrial damage, accumulation of intracellular/mitochondrial calcium, and apoptosis. Activation of B2R aggravates ROS generation, mitochondrial damage, and cell death induced by ATP depletion. These effects may act through the PLC-Ca(2+) signaling pathway.
...
PMID:Bradykinin enhances reactive oxygen species generation, mitochondrial injury, and cell death induced by ATP depletion--a role of the phospholipase C-Ca(2+) pathway. 1766 34

BBZDR/Wor rat is a new model of type II diabetes with spontaneous obesity and clinical characteristics close to human diabetes. In this study the time-course of cerebroarterial dysfunction was characterized. Posterior cerebral arteries from BBZDR/Wor rats and their age-matched lean controls were pressurized to 70 mm Hg in an arteriograph. Effects of intraluminal pressure and different pharmacological agents on myogenic tone were evaluated. Pressure-myogenic tone curves in diabetic arteries were similar to that in non-diabetic arteries at pre-diabetic age, showed leftward shift at 4 weeks and were significantly different with higher myogenic tone at 5 and 8 months of diabetes. Age-dependent decrease in myogenic tone was observed in non-diabetic arteries. Dilation to histamine was similar to that in non-diabetic arteries at pre-diabetic and at 4 weeks but significantly reduced at 5 and 8 months of diabetes. Bradykinin-mediated dilation was significantly reduced in early and chronic diabetes, whereas (+/-)-S-nitroso-N-acetylpenicillamine (SNAP)-mediated dilation was decreased modestly at 8 months of diabetes. Sensitivity and constriction to 5-hydroxytryptamine were increased in early and chronic diabetes. Responses to bradykinin and 5-hydroxytryptamine were decreased and increased, respectively. Myogenic tone was significantly less sensitive to (lower pIC(50)) U-73122 than normal arteries at 4 weeks and 8 months of diabetes suggesting an increased activation of phospholipase C (PLC). This study shows that pressure-mediated autoregulation of cerebral arteries in type II diabetes operates at higher resistance. Endothelium-dependent dilation was decreased with chronic diabetes with increased sensitivity to constrictor agonist. Endothelium-independent dilation was modestly affected. Arterial hyper-reactivity to pressure and constrictor agonist were likely due to increased PLC activation.
...
PMID:Myogenic tone and reactivity of cerebral arteries in type II diabetic BBZDR/Wor rat. 1803 20

With respect to functional aspects, the kallikrein-kinin-system can be divided into a plasma kallikrein-kinin-system and a tissue kallikrein-kinin-system. At least four functional kinin peptides act via two different G-protein-coupled receptors, an inducible B1-receptor and a constitutively expressed B2-receptor. B1R and B2R couple to G(q/11) and lead via phospholipase C to Ca2+ mobilization. In humans both, bradykinin and kallidin are agonists on the B2-receptor. In contrast, bradykinin is believed to be the only kinin acting on the B2R in rats and mice. However, recently we have isolated a kallidin-like-peptide from plasma and urine of rats. Until now the kinin ligand-receptor interactions were mainly characterized in binding studies. However, receptor affinity does not inevitably correspond with the intrinsic activity of an agonist. The aim of the present study was to investigate intracellular calcium mobilization to quantify mouse, rat and human B1- and B2-receptor activation by bradykinin, kallidin, des-Arg9-bradykinin, des-Arg10-kallidin, and of the two novel rat kinins, kallidin-like-peptide and des-Arg10-kallidin-like-peptide. In cells stably expressing the human, rat, and mouse B2-receptor, respectively, bradykinin, kallidin, and kallidin-like-peptide were nearly equipotent (EC50, 10(-12)M) at eliciting Ca2+-transients. Their des-Arg-derivatives were 10(3)-fold less potent. In cells expressing B1-receptor the des-Arg derivatives elicited Ca2+-signals at an EC50 in the order of 10(-9)M. Major differences between these peptides could not be observed. Bradykinin, kallidin, and kallidin-like-peptide caused a Ca2+-signal at substantially higher concentrations in the order of 10(-7)M. The data show that des-Arg9-bradykinin, des-Arg10-kallidin, and des-Arg10-kallidin-like-peptide are equipotent agonists at the B1-receptor. Bradykinin, kallidin and kallidin-like-peptide are equipotent agonists at the B2-receptor.
...
PMID:Ca2+ signalling of kinins in cells expressing rat, mouse and human B1/B2-receptor. 1818 40

Bradykinin is an inflammatory mediator that plays a pivotal role in pain and hyperalgesia in inflamed tissues by exciting and/or sensitizing nociceptors. TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain. Here, using electrophysiological, immunocytochemical and behavioural analyses, we showed a functional interaction of these two inflammation-related molecules in both heterologous expressing systems and primary sensory neurons. We found that bradykinin increased the TRPA1 currents evoked by allyl isothiocyanate (AITC) or cinnamaldehyde in HEK293 cells expressing TRPA1 and bradykinin receptor 2 (B2R). This potentiation was inhibited by phospholipase C (PLC) inhibitor or protein kinase A (PKA) inhibitor, and mimicked by PLC or PKA activator. The functional interaction between B2R and TRPA1, as well as the modulation mechanism, was also observed in rat dorsal root ganglia neurons. In an occlusion experiment, the PLC activator could enhance AITC-induced TRPA1 current further even in saturated PKA-mediated potentiation, indicating the additive potentiating effects of the PLC and PKA pathways. These data for the first time indicate that a cAMP-PKA signalling is involved in the downstream from B2R in dorsal root ganglia neurons in addition to PLC. Finally, subcutaneous pre-injection of a sub-inflammatory dose of bradykinin into rat hind paw enhanced AITC-induced pain behaviours, which was consistent with the observations in vitro. Collectively, these results represent a novel mechanism through which bradykinin released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.
...
PMID:Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain. 1835 88

Bradykinin (BK) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. It has been shown to induce interleukin-6 (IL-6) expression in inflammatory responses in rheumatoid arthritis. We investigated the signaling pathway involved in IL-6 production caused by BK in synovial fibroblasts. BK caused concentration- and time-dependent increases in IL-6 production. By using pharmacological inhibitors or genetic inhibition of the BK receptor, siRNA revealed that B2 but not B1 BK receptors are involved in BK-mediated up-regulation of IL-6. BK-mediated IL-6 production was attenuated by phospholipase C inhibitor (U73122), protein kinase Cdelta inhibitor (rottlerin), NF-kappaB inhibitor (PDTC), IkappaB protease inhibitor (TPCK) and NF-kappaB inhibitor peptide. Stimulation of synovial fibroblasts with BK activated IkappaB kinase alpha/beta (IKK alpha/beta), IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation at Ser(276), p65 and p50 translocation from the cytosol to the nucleus and kappaB-luciferase activity. BK mediated an increase of IKK alpha/beta and IkappaBalpha phosphorylation, kappaB-luciferase activity and p65 and p50 binding to the NF-kappaB element was inhibited by B2 BK receptor antagonist (HOE140), U73122 and rottlerin. Our results suggest that BK increased IL-6 production in synovial fibroblasts via the B2 BK receptor/PI-PLC/PKCdelta/and NF-kappaB signaling pathway.
...
PMID:Bradykinin-induced IL-6 expression through bradykinin B2 receptor, phospholipase C, protein kinase Cdelta and NF-kappaB pathway in human synovial fibroblasts. 1862 20

Transient receptor potential melastatin-7 (TRPM7) channels have recently been identified to be regulated by vasoactive agents acting through G protein-coupled receptors in vascular smooth muscle cells (VSMC). However, downstream targets and functional responses remain unclear. We investigated the subcellular localization of TRPM7 in VSMCs and questioned the role of TRPM7 in proinflammatory signaling by bradykinin. VSMCs from Wistar-Kyoto rats were studied. Cell fractionation by sucrose gradient and differential centrifugation demonstrated that in bradykinin-stimulated cells, TRPM7 localized in fractions corresponding to caveolae. Immunofluorescence confocal microscopy revealed that TRPM7 distributes along the cell membrane, that it has a reticular-type intracellular distribution, and that it colocalizes with flotillin-2, a marker of lipid rafts. Bradykinin increased expression of calpain, a TRPM7 target, and stimulated its cytosol/membrane translocation, an effect blocked by 2-APB (TRPM7 inhibitor) and U-73122 (phospholipase C inhibitor), but not by chelerythrine (PKC inhibitor). Expression of proinflammatory mediators VCAM-1 and cyclooxygenase-2 (COX-2) was time-dependently increased by bradykinin. This effect was blocked by Hoe-140 (B2 receptor blocker) and 2-APB. Our data demonstrate that in bradykinin-stimulated VSMCs: 1) TRPM7 is upregulated, 2) TRPM7 associates with cholesterol-rich microdomains, and 3) calpain and proinflammatory mediators VCAM-1 and COX2 are regulated, in part, via TRPM7- and phospholipase C-dependent pathways through B2 receptors. These findings identify a novel signaling pathway for bradykinin, which involves TRPM7. Such phenomena may play a role in bradykinin/B2 receptor-mediated inflammatory responses in vascular cells.
...
PMID:Bradykinin regulates calpain and proinflammatory signaling through TRPM7-sensitive pathways in vascular smooth muscle cells. 1879 34


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---