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

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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)

A preliminary model of the rat AT1A angiotensin II (AII) receptor (Joseph, M. P., Maigret, B., Bonnafous J.-C., Marie, J., and Scheraga, H. A. (1995) J. Protein Chem. 14, 381-398) has predicted an interaction between Asn111 located in transmembrane domain (TM) III and Tyr292 (TM VII) in the nonactivated receptor; a disruption of this interaction upon AII activation would allow Tyr292 to interact with the conserved Asp74 (TM II). The previous verification that Tyr292 is essential for receptor coupling to phospholipase C (Marie, J., Maigret, B., Joseph, M. P., Larguier, R., Nouet, S., Lombard, C., and Bonnafous, J.-C. (1994) J. Biol. Chem. 269, 20815-20818) prompted us to check the possible alterations in receptor properties upon Asn111 --> Ala mutation. The mutated receptor (N111A) displayed: (i) strong constitutive activity, with amplification of the maximal phospholipase C response to AII; (ii) agonist behavior of the AT2-specific ligand CGP 42112A, [Sar1, Ile8]AII, and [Sar1,Ala8]AII, antagonists of the wild-type receptor; (iii) inverse agonism behavior of the non-peptide ligands DuP 753, LF 7-0156, and LF 8-0129. The results are discussed in the light of the allosteric ternary complex models and other described examples of constitutive activation of G protein-coupled receptors.
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PMID:Mutation of Asn111 in the third transmembrane domain of the AT1A angiotensin II receptor induces its constitutive activation. 899 67

In previous studies, we showed that angiotensin II (Ang II) and its congener peptides-angiotensin-(2-8) [Ang-(2-8)] and angiotensin-(1-7) [Ang-(1-7)]-activate 2 distinct signal transduction pathways in a mixed population of human cortical astrocytoma cells. This suggested that different populations of astrocytes could be heterogeneous with respect to their expression of Ang II receptors or the responses to which these receptors are coupled. To compare the responses which are activated by Ang II and its congener peptides in astrocytes from different brain regions, we measured phospholipase C (PLC) activity and prostaglandin release in isolated astrocytes from 4 different areas of neonatal rat brain. In medullary and cerebellar astrocytes, Ang II activated a phosphoinositide-specific PLC in a dose-dependent manner with EC50s of 1.74 and 1.86 nM, respectively. Ang-(2-8) also caused an increase in inositol phosphate release. PLC activity was coupled to an AT1 receptor in both medullary and cerebellar astrocytes, as demonstrated by the inhibition of Ang II-activation of inositol phosphate release by the AT1 antagonist losartan. The AT2 antagonist PD 123319 was ineffective. Ang II and Ang-(2-8) also released prostacyclin from medullary and cerebellar astrocytes, measured as the release of its stable metabolite 6-keto-PGF1 alpha. In contrast, Ang II did not activate PLC or release prostaglandins in astrocytes isolated from the cortex or hypothalamus. In addition, Ang-(1-7) did not stimulate the release of inositol phosphates or prostacyclin in astrocytes from any of the neonatal rat brain regions examined. However, bradykinin (1 microM) activated PLC or released prostacyclin in astrocytes isolated from all 4 brain regions. These results suggest that Ang II receptors on region-specific astrocytes activate distinct signal transduction mechanisms in response to different angiotensin peptides.
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PMID:Angiotensin II activates distinct signal transduction pathways in astrocytes isolated from neonatal rat brain. 909 77

1. Angiotensin II (Ang II), the main effector of the renin-angiotensin system, exerts its vasoconstrictory and trophic actions on smooth muscle cells via AT1 receptors. However, Ang II does not act only on smooth muscle cells, as Ang II receptors are also present in endothelial cells. 2. The receptor type on these cells differs depending on the origin of the endothelium and the species. The rat endothelial receptors are mostly of the AT1 type, but AT2 receptors have also been found. The pharmacological characteristics of the AT1 receptors on endothelial cells are similar to those of other cell types. 3. Ang II stimulates phospholipase C and phospholipase A2 activation via the AT1 receptor in endothelial cells. Ang II also stimulates the tyrosine phosphorylation of several proteins in these cells. 4. Some studies suggest that the AT1 receptor mediates the release of vasodilator molecules by endothelial cells and could modulate Ang II effect on smooth muscle cells. Ang II may also inhibit endothelial cell growth via the AT2 receptor. Finally, endothelial Ang II receptors may be implicated in the regulation of fibrinolysis.
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PMID:Angiotensin II receptors in endothelial cells. 934 11

Using an in situ perfusion technique of isolated left rat adrenal gland, it has been demonstrated that angiotensin-II (ANG-II) increases DNA synthesis in the zona glomerulosa (ZG), but not fasciculata-reticularis cells. The AT1 receptor antagonist DuP753 abolished the effect of ANG-II, while the AT2 receptor antagonist PD 123319 potentiated it. Both Ro31-8220, an inhibitor of protein kinase C (PKC), and tyrphostin-23, an inhibitor of tyrosine kinase (TK), evoked a partial reversal of ANG-II effect, and when added together to the perfusion medium abolished it. In contrast, the phospholipase C inhibitor U-73122 alone was able to induce a complete blockade of ANG-II effect. Neither the phospholipase A2 inhibitor AACOCF3 nor the cyclooxygenase inhibitor indomethacin and the lipoxygenase inhibitor phenidone affected ANG-II-induced stimulation of DNA synthesis, thereby making unlikely the involvement of the arachidonic acid signaling pathways. Our findings suggest that (i) ANG-II stimulates rat ZG cell proliferation acting via AT1 receptors coupled with phospholipase C, which activates both PKC and TK signaling systems; and (ii) the proliferogenic effect of ANG-II is partially counteracted by the activation of the AT2 receptor subtype.
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PMID:Angiotensin-II stimulates DNA synthesis in rat adrenal zona glomerulosa cells: receptor subtypes involved and possible signal transduction mechanism. 937 6

Angiotensin II (AngII), a circulating vasoactive peptide, interacts with specific membrane-bound receptors on the target tissues (vessels, kidneys and adrenal gland). Using new pharmacological tools and molecular cloning, these receptors have been classified in two types, called AT1 et AT2, whereas two subtypes, called AT1A et AT1B, have been identified for the rodent AT1 receptors, but not in humans. All these receptors present a seven hydrophobic transmembrane domain structure, which is classical for G protein coupled receptors. The interspecies molecular homology of these AngII receptors is high (> 90 per cent identity) within the same type of receptor, but is rather low (approximately 35 per cent identity) between the two types of receptors. The AT1 receptors are responsible for most of the AngII physiological actions and are coupled to a Gq protein, which activates a phospholipase C producing second messengers which activate protein kinases C and mobilize calcium intracellular stores. More recently, a strong interaction of this receptor has been demonstrated with the signalling pathways of the tyrosine kinases. The molecular mechanisms and the physiological importance of these interactions remain to be elucidated. The intracellular signalling (Gi coupling and tyrosine phosphatase activation) and the physiological actions (cellular differentiation, apoptosis) of the AT2 receptors are more controversial.
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PMID:[Angiotensin II receptors: classification, structure, and signal transduction]. 977 19

Angiotensin II (Ang II) receptors are 7 transmembrane domain receptors corresponding to 2 pharmacologically and molecularly distinct receptors, called AT1 and AT2, the primary structures of which have been established by molecular cloning. Most if not all the physiological actions of Ang II are mediated by the AT1 receptor, which is coupled to a Gq protein activating a phospholipase C (PLC), which in turn mobilizes the intracellular calcium stores and activates protein kinases C. Many site directed mutagenesis works have allowed to identify short extracellular sequences responsible for the Ang II binding, whereas non-peptidic AT1-specific antagonists bind to a different transmembranar site. Structural modifications are responsible for the change of the receptor from an inactive to an active state. At the basal state, the receptor is mostly in an inactive state; agonists present a better affinity for the active state, displacing the equilibrium to this state; at the opposite, the inverse agonists present a better affinity for the inactive state. Antagonists present a similar affinity for both states of the receptor. Several mutations of polar residues of the transmembrane domains block the receptor either in an inactive state (D74D, S115A, Y292F) or in a constitutively active state (N111A and N295A). After activation, the receptor is coupled to different intracellular proteins, the first of them being the G proteins of the Gq/11 family. The sequences of the receptor involved in this coupling correspond to the 2nd, the 3rd intracellular loops and the proximal segment of the carboxyterminal domain. Other sequences interact with other proteins, such as the 319YIPP332 sequence of the carboxyterminus, which interacts with the Jak2 tyrosine kinase. After the binding of a peptidic ligands, the ligand-receptor complex is internalized independently for the G protein coupling. Again, site directed mutagenesis experiments have localized a sequence of the carboxyterminus (329STLSTKMSTLS338) involved in the internalization. This serine and threonine-rich sequence plays also a role in the desensitization of the AT1 receptor, consecutively to its phosphorylation. The AT2 receptor is only 34% identical to the AT1 receptor and its functions are far less understood. Its physiological functions (apoptosis and antiproliferative actions) and its signaling pathways (activation of Gi proteins and tyrosine phosphatases) are still a matter of debate.
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PMID:[Molecular structure and function of angiotensin ii receptors]. 985 75

Angiotensin II (Ang II) receptor subtypes AT1 and AT2 share 34% overall homology, but the least homology is in their third intracellular loop (3rd ICL). In an attempt to elucidate the role of the 3rd ICL in determining the similarities and differences in the functions of the AT1 and the AT2 receptors, we generated a chimeric receptor in which the 3rd ICL of the AT2 receptor was replaced with that of the AT1 receptor. Ligand-binding properties and signaling properties of this receptor were assayed by expressing this receptor in Xenopus oocytes. Ligand-binding studies using [125I-Sar1-Ile8] Ang II, a peptidic ligand that binds both the AT1 and the AT2 receptor subtypes, and 125I-CGP42112A, a peptidic ligand that is specific for the AT2 receptor, showed that the chimeric receptor has lost affinity to both ligands. However, IP3 levels of the oocytes expressing the chimeric receptor were comparable to the IP3 levels of the oocytes expressing the AT1 receptor, suggesting that the chimeric receptors could couple to phospholipase C pathway in response to Ang II. We have shown previously that the nature of the amino acid present in the position 215 located in the fifth transmembrane domain (TMD) of the AT2 receptor plays an important role in determining its affinity to different ligands. Our results from the ligand-binding studies of the chimeric receptor further support the idea that the structural organization of the region spanning the 5th TMD and the 3rd ICL of the AT2 receptor has an important role in determining the ligand-binding properties of this receptor.
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PMID:Role of the third intracellular loop of the angiotensin II receptor subtype AT2 in ligand-receptor interaction. 1006 67

The purpose of this study was to characterize the nature and mechanisms of angiotensin II-evoked calcium signaling in AR42J cells. Cytosolic calcium concentrations were determined using fura-2-based microfluorimetry. Angiotensin II causes elevations in free cytosolic calcium ([Ca2+]i) in the rat pancreatic acinar cell line AR42J. The mechanisms of angiotensin II-evoked calcium signaling were examined using fura-2-based fluorescent digital microscopy. Angiotensin II caused dose-dependent increments in [Ca2+]i over a concentration range of 0.1-1,000 nM, with an average increment of 243 +/- 16 nM at an angiotensin II concentration of 1,000 nM. Dup753, an AT1-specific antagonist, inhibited angiotensin II-evoked signaling, whereas the AT2 antagonist PD123,319 had no effect. Preincubation with the phospholipase C inhibitor U73122 reduced the response in [Ca2+]i to 25% of that of the control. Thapsigargin abolished angiotensin II-evoked calcium signaling. The inositol 1,4,5-trisphosphate receptor antagonist heparin introduced by radiofrequency electroporation inhibited responses to 46 +/- 6% of controls. Angiotensin II-evoked signals were reduced in magnitude and duration by elimination of Ca2+ from the extracellular buffer. Preincubation with pertussis toxin (100 ng/ml) had no effect. Angiotensin II did not stimulate cyclic AMP or suppress vasoactive intestinal peptide stimulated cyclic AMP production over the concentration range that caused Ca2+ signaling.
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PMID:Calcium signaling induced by angiotensin II in the pancreatic acinar cell line AR42J. 1009 Apr 17

Different signal transduction pathways, i.e. Ca2+- and cAMP-dependent, involved in mediating the effects of angiotensin II (AII) were investigated separately using the short-circuit current (Isc) technique and radioimmunoassay (RIA) in a cystic fibrosis pancreatic cell line (CFPAC-1) which exhibits defective cAMP-dependent but intact Ca2+-dependent anion secretion. The AII-induced Isc could be inhibited by the specific antagonist for AT1, losartan (1 microM), but not the antagonist for AT2, PD123177 (up to 10 microM). The AII-induced Isc was also reduced by the treatment of the cells with a Ca2+ chelator, BAPTA-AM (100 microM), indicating a dependence of the AII-induced anion secretion on the intracellular Ca2+. Treatment of the cells with pertussis toxin (0.1 microg/ml) or a phospholipase C (PLC) inhibitor, U73122 (5 microM), resulted in a substantial reduction in the AII-induced Isc indicating involvement of Gi and PLC in the Ca2+-dependent anion secretion. RIA measurements showed that AII stimulated an increase in cAMP production which could be reduced by losartan, pertussis toxin and U73122 but not BAPTA-AM. In addition, inhibitors of cyclooxygenase, indomethacin (10 microM) and piroxicam (10 microM), did not have any effect on the AII-induced cAMP production, excluding the involvement of prostaglandins. Our results suggest that both AII-stimulated cAMP and Ca2+-dependent responses are mediated by the AT1 receptor and Gi-coupled PLC pathway. However, the AII-stimulated cAMP production in CFPAC-1 cells is not dependent on Ca2+ or the formation of prostaglandins.
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PMID:Angiotensin II-mediated signal transduction events in cystic fibrosis pancreatic duct cells. 1020 4

Angiotensin (A) II is a potent constrictor as well as growth stimulant of vascular smooth muscle cell caused by activation of AT1 receptor signal transduction systems. There are two major signal systems of AT1 receptor: one leads to an increase in cytosolic free calcium levels causing smooth muscle contraction which may result in high blood pressure, and the other leads to smooth muscle proliferation and inflammation which may result in atherosclerosis. AT1 receptor activation induces phosphinositide hydrolysis by phospholipase C and creates an inositol phosphate, which release calcium from cytosolic calcium pools. Cytosolic calcium can also be elevated by activation of calcium channel via a link between AT1 receptor and a G protein. Protein phosphorylation triggered by AT1 receptor is important for cell growth, in which tyrosine kinase, serine/threonine kinase and protein kinase C are involved. Free radicals are generated by NADH/NADPH oxidase in response to AT1 receptor activation, causing expression of genes leading to atherosclerosis. On the other hand, activation of AT2 receptor is shown to play a role of lowering blood pressure. Some phosphatases and NO/cyclic GMP would be involved in the mechanism. In renal vasculature, endothelium dependent epoxygenase products are synthesized by AT2 receptor stimulation causing vasorelaxation. In summary, AT1 receptor signals are vasopressive and evoke atherosclerosis, whereas AT2 receptor signals may possibly be vasodilatory.
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PMID:[Signal transduction systems of angiotensin II receptors]. 1036 37


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