Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kidney is an important target organ for angiotensin II. The diverse biologic effects of angiotensin II in the kidney and periphery suggest that angiotensin II may be interacting with more than one receptor. Recently, the synthesis of highly selective nonpeptide angiotensin II receptor antagonists and the expression cloning of the angiotensin receptor have unequivocally demonstrated the existence of at least two angiotensin II receptor subtypes, designated AT1 and AT2. Autoradiography and ligand binding studies have shown that most tissues, including the kidney, have a mixture of both receptor subtypes. The AT1 receptor is coupled via G proteins to traditional signal transduction mechanisms such as stimulation of phospholipase C, Ca2+ mobilization, and inhibition of adenylate cyclase. The AT2 receptor does not appear to be coupled to G proteins, and the signal transduction pathway(s) associated with this receptor is not known but may involve cGMP. In the kidney, as in the periphery, all of the major physiologic actions of angiotensin II appear to be mediated by activation of the AT1 receptor. In this review, the general characteristics of the AT1 and AT2 receptors and their distribution and function in the kidney will be discussed.
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PMID:Angiotensin II receptor subtypes in the kidney. 831 80

Angiotensin II stimulates proximal tubule acidification by activating both the Na-H antiporter and the Na-HCO3 cotransporter. The mechanism whereby angiotensin II stimulates the Na-HCO3 cotransporter was investigated in renal cortical basolateral membrane vesicles of the rabbit by measuring 22Na uptake in the presence of HCO3 and gluconate. Na-HCO3 cotransporter activity (expressed in nanomoles per milligram of protein per 3 s) was taken as the difference in 22Na uptake in the presence of HCO3 and gluconate. Angiotensin II stimulated Na-HCO3 cotransporter activity significantly (control, 1.5 +/- 0.4; angiotensin II, 3.3 +/- 0.6; P < 0.05), and this stimulation was prevented by the angiotensin II receptor antagonist DuP 753. Angiotensin II has been shown to stimulate both pertussis toxin-sensitive Gi protein and pertussis toxin-insensitive Gq protein. In the presence of pertussis toxin, angiotensin II (10(-11) M) failed to stimulate the Na-HCO3 cotransporter, suggesting a role of Gi protein in mediating this effect. In the presence of a polyclonal antibody against Gi protein, angiotensin II failed to stimulate the Na-HCO3 cotransporter (control, 1.6 +/- 0.4; angiotensin II, 3.9 +/- 0.9; angiotensin II + Gi, 1.2 +/- 0.7). Angiotensin II stimulated inositol triphosphate release, and this effect could be blocked by the phospholipase C inhibitor U73122, suggesting a role of phospholipase C or A2 in this effect of angiotensin II. In the presence of the protein kinase C inhibitor calphostin C (50 nM), angiotensin II also failed to stimulate the Na-HCO3 cotransporter. These results demonstrate that angiotensin II stimulates the renal Na-HCO3 cotransporter by interacting with a specific angiotensin II receptor and that this stimulation is mediated by the activation of Gi and Gq proteins.
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PMID:Regulation of the renal Na-HCO3 cotransporter: IV. Mechanisms of the stimulatory effect of angiotensin II. 858 87

Angiotensin II stimulates DNA synthesis in aortic smooth muscle cells prepared from spontaneously hypertensive rats, with maximal levels detected 20 h after stimulation. Angiotensin II receptor antagonists inhibited the angiotensin II-induced DNA synthesis. In particular, the noncompetitive antagonist 2-ethoxy-1-[[2'(1 H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid (CV11974) was more effective than expected from its affinity for the angiotensin II receptor and its potency for inhibiting angiotensin II-induced increase in cytosolic free Ca2+ concentration 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl) methyl]imidazole, potassium salt (losartan), one of the antagonists, inhibited angiotensin II-induced DNA synthesis by 92% and 79%, even when added 2 and 4 h after angiotensin II stimulation, respectively. Angiotensin II also increases the mRNA of platelet-derived growth factor-A chain and basic fibroblast growth factor. The increase was observed within 4 h after angiotensin II stimulation. In this case, the addition of losartan at 4 h after angiotensin II stimulation hardly influenced the time course of the mRNA level of growth factors. Also, conditioned media of cells stimulated with angiotensin II did not influence DNA synthesis in the presence of CV11974. These results suggest that sustained receptor stimulation with angiotensin II is required for DNA synthesis in addition to the early intracellular signaling following phospholipase C activation in a manner independent of the induction of growth factors such as platelet-derived growth factor-AA and basic fibroblast growth factor.
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PMID:A long-term receptor stimulation is requisite for angiotensin II-dependent DNA synthesis in vascular smooth muscle cells from spontaneously hypertensive rats. 871 28

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.
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PMID:The renin-angiotensin system and vascular hypertrophy. 883 52

A general model for membrane receptor action mechanisms indicates that information detected by receptors in the cell plasma membrane is transmitted to biological effectors, normally mediated by coupling elements. Seven-site transmembrane receptors coupled to G-proteins likely represent the most conserved and diversified category of membrane receptors. Information transfer from the extracellular medium to the cell involves three membrane proteins: a receptor, a G-protein (which binds and hydrolyzes GTP during its cycle), and an effector that regulates intracellular ion levels or second messengers. They detect various messages: light emissions, odorant molecules, peptide hormones, neurotransmitters and proteins. Structures of these membrane proteins include an extracellular N-terminal part, seven transmembrane alpha-helices and an intracellular C-terminal part. They are coupled to a G-protein which is stimulated upon ligand-induced receptor activation. This activated G-protein exchanges a GDP molecule for a GTP molecule which in turn acts on the effector. The effector is an enzyme (adenylate cyclase, phospholipase C, etc.) or an ionic channel (K+, Ca++ channels, etc.). Recognition of the message (which is specified by the membrane receptor), following amplification through activation of several catalytic cycles of G-proteins and the effector, thus leads to cellular events: modification of genetic transcription, cell growth, intercellular communication and modulation of the membrane potential. The present article briefly summarizes results on this topic with special stress on the angiotensin II receptor which is currently being investigated in our laboratory.
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PMID:[Cellular information and communication: receptors coupled to g-proteins]. 929 62

Folliculo-stellate cells of the anterior pituitary are thought to modulate pituitary hormone secretion through a paracrine mechanism. Angiotensin II and pituitary adenylate cyclase-activating polypeptide (PACAP) have previously been shown to increase the intracellular Ca2+ concentration ([Ca2+]i) of these cells. In the present study, we examined the effects of various peptides such as bradykinin, angiotensin II, endothelin-1, PACAP, galanin and neurotensin by Ca2+-imaging of folliculo-stellate cells in primary culture. Bradykinin and angiotensin II increased [Ca2+]i in folliculo-stellate cells. Both responses were completely suppressed by thapsigargin and were significantly suppressed by the phospholipase C inhibitor, U-73122. Ryanodine did not significantly modify the responses. A B2 antagonist and angiotensin II receptor antagonist inhibited the response induced by bradykinin and angiotensin II, respectively. Endothelin-1 and PACAP increased [Ca2+]i in fewer than 50% of folliculo-stellate cells but galanin and neurotensin did not influence [Ca2+]i in any of the folliculo-stellate cells tested. These results indicate that bradykinin and angiotensin II increase [Ca2+]i in folliculo-stellate cells by activating phospholipase C through B2 receptor and AT1 receptor, respectively, and that endothelin-1 and PACAP also increase [Ca2+]i in some folliculo-stellate cells.
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PMID:Bradykinin and angiotensin II-induced [Ca2+]i rise in cultured rat pituitary folliculo-stellate cells. 1173 52

Despite the central physiological function of the myogenic response, the underlying signalling pathways and the identity of mechanosensors in vascular smooth muscle (VSM) are still elusive. In contrast to present thinking, we show that membrane stretch does not primarily gate mechanosensitive transient receptor potential (TRP) ion channels, but leads to agonist-independent activation of G(q/11)-coupled receptors, which subsequently signal to TRPC channels in a G protein- and phospholipase C-dependent manner. Mechanically activated receptors adopt an active conformation, allowing for productive G protein coupling and recruitment of beta-arrestin. Agonist-independent receptor activation by mechanical stimuli is blocked by specific antagonists and inverse agonists. Increasing the AT(1) angiotensin II receptor density in mechanically unresponsive rat aortic A7r5 cells resulted in mechanosensitivity. Myogenic tone of cerebral and renal arteries is profoundly diminished by the inverse angiotensin II AT(1) receptor agonist losartan independently of angiotensin II (AII) secretion. This inhibitory effect is enhanced in blood vessels of mice deficient in the regulator of G-protein signalling-2. These findings suggest that G(q/11)-coupled receptors function as sensors of membrane stretch in VSM cells.
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PMID:Gq-coupled receptors as mechanosensors mediating myogenic vasoconstriction. 1912 60

Inflammasomes activate caspase-1 in response to molecular signals from pathogens and other dangerous stimuli as a part of the innate immune response. A previous study discovered a small-molecule, 4-fluoro- N'-[1-(2-pyridinyl)ethylidene]benzohydrazide, which we named DN1, that reduces the cytotoxicity of anthrax lethal toxin (LT). We determined that DN1 protected cells irrespectively of LT concentration and reduced the pathogenicity of an additional bacterial exotoxin and several viruses. Using the LT cytotoxicity pathway, we show that DN1 does not prevent LT internalization and catalytic activity or caspase-1 activation. Moreover, DN1 does not affect the proteolytic activity of host cathepsin B, which facilitates the cytoplasmic entry of toxins. PubChem Bioactivities lists two G protein-coupled receptors (GPCR), type-1 angiotensin II receptor and apelin receptor, as targets of DN1. The inhibition of phosphatidylinositol 3-kinase, phospholipase C, and protein kinase B, which are downstream of GPCR signaling, synergized with DN1 in protecting cells from LT. We hypothesize that DN1-mediated antagonism of GPCRs modulates signal transduction pathways to induce a cellular state that reduces LT-induced pyroptosis downstream of caspase-1 activation. DN1 also reduced the susceptibility of Drosophila melanogaster to toxin-associated bacterial infections. Future experiments will aim to further characterize how DN1 modulates signal transduction pathways to inhibit pyroptotic cell death in LT-sensitive macrophages. DN1 represents a novel chemical probe to investigate host cellular mechanisms that mediate cell death in response to pathogenic agents.
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PMID:Role of a Small Molecule in the Modulation of Cell Death Signal Transduction Pathways. 3035 48


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