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)

Pulmonary arteries (PA) are resistant to the vasodilator effects of extracellular acidosis in systemic vessels; the mechanism underlying this difference between systemic and pulmonary circulations has not been elucidated. We hypothesized that RhoA/Rho-kinase-mediated Ca2+ sensitization pathway played a greater role in tension development in pulmonary than in systemic vascular smooth muscle and that this pathway was insensitive to acidosis. In arterial rings contracted with the alpha1-agonist phenylephrine (PE), the Rho-kinase inhibitor Y-27632 (< or =3 microM) induced greater relaxation in precontracted PA rings than in aortic rings. In PA rings stimulated by PE, the activation of RhoA was greater than in aorta. Normocapnic acidosis (NA) induced a smaller relaxation in precontracted PA than in aorta. However, in the presence of nifedipine and thapsigargin, when PE-induced contraction was predominantly mediated by Rho-kinase, the relaxant effect of NA was reduced and similar in both vessel types. Furthermore, in the presence of Y-27632, NA induced a greater relaxation in both PA and aorta, which was similar in both vessels. Finally, in alpha-toxin-permeabilized smooth muscle, PE-induced contraction at constant Ca2+ activity was inhibited by Y-27632 and unaffected by acidosis. These results indicate that Ca2+ sensitization induced by the RhoA/Rho-kinase pathway played a greater role in agonist-induced vascular smooth muscle contraction in PA than in aorta and that tension mediated by this pathway was insensitive to acidosis. The predominant role of the RhoA/Rho-kinase pathway in the pulmonary vasculature may account for the resistance of this circulation to the vasodilator effect of acidosis observed in the systemic circulation.
...
PMID:Effect of changes in pH on wall tension in isolated rat pulmonary artery: role of the RhoA/Rho-kinase pathway. 1476 67

Although muscarinic acetylcholine receptors (mAChRs) regulate proliferation in many cell types, the signaling pathways involved are unclear. The participation of the small GTPases Rac1 and RhoA in M(3) mAChR-mediated inhibition of proliferation was investigated by activating M(3) mAChRs stably transfected in Chinese hamster ovary cells stably coexpressing hemagglutinin (HA)-tagged wild-type or mutant Rac1 or RhoA proteins. Activation of M(3) mAChRs activates both Rac1 and RhoA and inhibits cell proliferation in all cell lines tested. mAChR-mediated inhibition of proliferation is diminished in cells expressing dominant-negative HA-Rac1(Asn17) (m3DNRac) but is enhanced in cells expressing HA-Rac1 (m3WTRac) or constitutively active HA-Rac(Val12) (m3CARac). The activation of mAChRs in m3WTRac and m3CARac cells also induces apoptosis. Expression of wild-type or mutant RhoA proteins does not alter mAChR-mediated inhibition of proliferation. mAChR-induced inhibition of proliferation is abrogated in all cell lines when Galpha(q/11) signaling is terminated by transient expression of the COOH-terminal fragment of phospholipase C (PLC-beta1ct), the NH(2)-terminal fragment of G protein-coupled receptor kinase, or the regulator of G protein signaling 2. Pretreatment of all cells expressing wild-type or mutant Rac1 proteins with edelfosine, a phosphatidylinositol-specific PLC inhibitor, or Go 6976, which inhibits conventional protein kinase C (PKC) isoforms, diminishes the M(3) mAChR's ability to inhibit proliferation. Our results identify Galpha(q/11), PLC, and PKC as participants in the M(3) mAChR-mediated inhibition of cell proliferation. These findings indicate that in the context of high Rac1 activity, but not RhoA activity, M(3) mAChR-mediated activation of these participants triggers cell death.
...
PMID:Elevated Rac1 activity changes the M3 muscarinic acetylcholine receptor-mediated inhibition of proliferation to induction of cell death. 1510 36

G-protein-coupled receptors signal through Rho to induce actin cytoskeletal rearrangement. We previously demonstrated that thrombin stimulates Rho-dependent process retraction and rounding of 1321N1 astrocytoma cells. Surprisingly, while lysophosphatidic acid (LPA) activated RhoA in 1321N1 cells, it failed to produce cell rounding. Thrombin, unlike LPA, decreased Rac1 activity, and activated (GTPase-deficient) Rac1 inhibited thrombin-stimulated cell rounding, while expression of dominant-negative Rac1 promoted LPA-induced rounding. LPA and thrombin receptors appear to differ in coupling to Gi, as LPA but not thrombin-stimulated 1321N1 cell proliferation was pertussis toxin-sensitive. Blocking Gi with pertussis toxin enabled LPA to induce cell rounding and to decrease activated Rac1. These data support the hypothesis that Rac1 and Gi activation antagonize cell rounding. Thrombin and LPA receptors also differentially activated Gq pathways as thrombin but not LPA increased InsP3 formation and reduced phosphatidylinositol 4,5-bisphosphate (PIP2) levels. Microinjection of the plekstrin homology domain of phospholipase C (PLC)delta1, which binds PIP2, enabled LPA to elicit cell rounding, consistent with a requirement for PIP2 reduction. We suggest that Rho-mediated cytoskeletal responses are enhanced by concomitant reductions in cellular levels of PIP2 and Rac1 activation and thus effected only by G-protein-coupled receptors with appropriate subsets of G protein activation.
...
PMID:Rho-mediated cytoskeletal rearrangement in response to LPA is functionally antagonized by Rac1 and PIP2. 1544 83

Several recent studies have implicated the RhoA-Rho kinase pathway in arterial myogenic behavior. The goal of this study was to determine the effects of Rho kinase inhibition (Y-27632) on cerebral artery calcium and diameter responses as a function of transmural pressure. Excised segments of rat posterior cerebral arteries (100-200 microm) were cannulated and pressurized in an arteriograph at 37 degrees C. Increasing pressure from 10 to 60 mmHg triggered an elevation of cytosolic calcium concentration ([Ca(2+)](i)) from 113 +/- 9 to 199 +/- 12 nM and development of myogenic tone. Further elevation of pressure to 120 mmHg induced only a minor additional increase in [Ca(2+)](i) and constriction. Y-27632 (0.3-10 microM) inhibited myogenic tone in a concentration-dependent manner at 60 and 120 mmHg with comparable efficacy; conversely, sensitivity was decreased at 120 vs. 60 mmHg (50% inhibitory concentration: 2.5 +/- 0.3 vs. 1.4 +/- 0.1 microM; P < 0.05). Dilation was accompanied by further increases in [Ca(2+)](i) and an enhancement of Ca(2+) oscillatory activity. Y-27632 also effectively dilated the vessels permeabilized with alpha-toxin in a concentration-dependent manner. However, dilator effects of Y-27632 at low concentrations were larger at 60 vs. 100 mmHg. In summary, the results support a significant role for RhoA-Rho kinase pathway in cerebral artery mechanotransduction of pressure into sustained vasoconstriction (myogenic tone and reactivity) via mechanisms that augment smooth muscle calcium sensitivity. Potential downstream events may involve inhibition of myosin phosphatase and/or stimulation of actin polymerization, both of which are associated with increased smooth muscle force production.
...
PMID:Effects of Rho kinase inhibition on cerebral artery myogenic tone and reactivity. 1562 53

The monomeric GTPase RhoA, which is a key regulator of numerous cellular processes, is activated by a variety of G protein-coupled receptors, through either G12 or G(q) family proteins. Here we report that p63RhoGEF, a recently identified RhoA-specific guanine nucleotide exchange factor, enhances the Rho-dependent gene transcription induced by agonist-stimulated G(q/11)-coupled receptors (M3-cholinoceptor, histamine H1 receptor) or GTPase-deficient mutants of G alpha(q) and G alpha11. We further demonstrate that active G alpha(q) or G alpha11, but not G alpha12 or G alpha13, strongly enhances p63RhoGEF-induced RhoA activation by direct protein-protein interaction with p63RhoGEF at its C-terminal half. Moreover, the activation of p63RhoGEF by G alpha(q/11) occurs independently of and in competition to the activation of the canonical G alpha(q/11) effector phospholipase C beta. Therefore, our results elucidate a new signaling pathway by which G alpha(q/11)-coupled receptors specifically induce Rho signaling through a direct interaction of activated G alpha(q/11) subunits with p63RhoGEF.
...
PMID:The guanine nucleotide exchange factor p63RhoGEF, a specific link between Gq/11-coupled receptor signaling and RhoA. 1563 74

Contraction of esophageal (Eso) and lower esophageal sphincter (LES) circular muscle depends on distinct signal-transduction pathways. ACh-induced contraction of Eso muscle is linked to phosphatidylcholine metabolism, production of diacylglycerol and arachidonic acid (AA), and activation of the Ca(2+)-insensitive PKCepsilon. Although PKCepsilon does not require Ca(2+) for activation, either influx of extracellular Ca(2+) or release of Ca(2+) from stores is needed to activate the phospholipases responsible for hydrolysis of membrane phospholipids and production of second messengers, which activate PKCepsilon. In contrast, the LES uses two distinct intracellular pathways: 1) a PKC-dependent pathway activated by low doses of agonists or during maintenance of spontaneous tone, and 2) a Ca(2+)-calmodulin-myosin light chain kinase (MLCK)-dependent pathway activated in response to maximally effective doses of agonists during the initial phase of contraction. The Ca(2+) levels, released by agonist-induced activity of phospholipase C, determine which contractile pathway is activated in the LES. The Ca(2+)-calmodulin-MLCK-dependent contractile pathway has been well characterized in a variety of smooth muscles. The steps linking activation of PKC to myosin light chain (MLC20) phosphorylation and contraction, however, have not been clearly defined for LES, Eso, or other smooth muscles. In addition, in LES circular muscle, a low-molecular weight pancreatic-like phospholipase A2 (group I PLA2) causes production of AA, which is metabolized to prostaglandins and thromboxanes. These AA metabolites act on receptors linked to heterotrimeric G proteins to induce activation of phospholipases and production of second messengers to maintain contraction of LES circular muscle. We have examined the signal-transduction pathways activated by PGF(2alpha) and by thromboxane analogs during the initial contractile phase and found that these pathways are the same as those activated by other agonists. In response to low doses of agonists or during maintenance of tone, presumably due to low levels of calcium release, a PKC-dependent pathway is activated, whereas at high doses of PGF(2alpha) and thromboxane analogs, in the initial phase of contraction, calmodulin is activated, PKC activity is reduced, and contraction is mediated, in part, through a Ca(2+)-calmodulin-MLCK-dependent pathway. The PKC-dependent signaling pathways activated by PGF(2alpha) and by thromboxanes during sustained LES contraction, however, remain to be examined, but preliminary data indicate that a distinct PKC-dependent pathway may be activated during maintenance of tonic contraction, which is different from the one activated during the initial contractile response. The initial contractile response to low levels of agonists depends on activation of G(q). Sustained contraction in response to PGF(2alpha) may involve activation of the monomeric G protein RhoA, because the contraction is inhibited by the RhoA-kinase antagonist Y27632. This shift in signal-transduction pathways between initial and sustained contraction has been recently reported in intestinal smooth muscle.
...
PMID:Signal-transduction pathways that regulate smooth muscle function I. Signal transduction in phasic (esophageal) and tonic (gastroesophageal sphincter) smooth muscles. 1570 19

In this study, we show that IFNalpha increases the chemotaxis of human B cells to CCL20, CCL21 and CXCL12 in a dose- and time-dependent manner. The effect was maximal with 2000 IU ml(-1) IFNalpha. It peaked at 24 h and decreased thereafter. At 24 h, IFNalpha had increased B-cell chemotaxis to CCL20 by 20 +/- 6.2% (n = 9, P < 0.002), to CCL21 by 20 +/- 8.5% (n = 14, P < 0.0001) and to CXCL12 by 16.3 +/- 4.2% (n = 12, P < 0.003) without changing CCR6, CCR7 or CXCR4 expression. IFNalpha enhanced the migration of memory B cells to CCL20, CCL21 and CXCL12 2.6-fold more strongly than that of naive B cells. The triggering of chemokine receptors by their ligands resulted in the activation of phosphatidylinositide-3 kinase (PI3K)/protein kinase B (PKB), inhibitory NF-kappaB (IkappaBalpha) RhoA and extracellular signal-regulated protein kinase 1/2 (ERK1/2). All these effectors except ERK1/2 are crucial for B-cell chemotaxis. IFNalpha modulated the requirements for B-cell chemotaxis, which became dependent on ERK1/2, more dependent on PI3K, RhoA and nuclear factor-kappaB but less dependent on Gbetagamma and phospholipase C activation. IFNalpha also decreased ligand-induced chemokine receptor internalization in a manner dependent on PI3K/AKT and RhoA but not on IkappaBalpha and ERK1/2. Our data characterize chemokine receptor signaling in human B cells and clarify the relevance of downstream pathways in B-cell chemotaxis and chemokine receptor internalization. They also suggest that non-class I PI3K are involved in B-cell chemotaxis.
...
PMID:IFN{alpha} enhances human B-cell chemotaxis by modulating ligand-induced chemokine receptor signaling and internalization. 1574 30

It has been demonstrated that CPI-17 provokes an inhibition of myosin light chain phosphatase to increase myosin light chain phosphorylaton and Ca(2+) sensitivity during contraction of vascular smooth muscle. However, expression and agonist-mediated regulation of CPI-17 in bronchial smooth muscle have not been documented. Thus, expression and phosphorylation of CPI-17 mediated by PKC and ROCK were investigated using rat bronchial preparations. Acetylcholine (ACh)-induced contraction and Ca(2+) sensitization were both attenuated by 10(-6) mol Y-27632 /L, a ROCK inhibitor, 10(-6) mol calphostin C/L, a PKC inhibitor, and their combination. A PKC activator, PDBu, induced a Ca(2+) sensitization in alpha-toxin-permeabilized bronchial smooth muscle. In this case, the Ca(2+) sensitizing effect was significantly inhibited by caphostin C but not by Y-27632. An immunoblot study demonstrated CPI-17 expression in the rat bronchial smooth muscle. Acetylcholine induced a phosphorylation of CPI-17 in a concentration-dependent manner, which was significantly inhibited by Y-27632 and calphostin C. In conclusion, these data suggest that both PKC and ROCK are involved in force development, Ca(2+) sensitization, and CPI-17 phosphorylation induced by ACh stimulation in rat bronchial smooth muscle. As such, RhoA/ROCK, PKC/CPI-17, and RhoA/ROCK/CPI pathways may play important roles in the ACh-induced Ca(2+) sensitization of bronchial smooth muscle contraction.
...
PMID:Acetylcholine-induced phosphorylation of CPI-17 in rat bronchial smooth muscle: the roles of Rho-kinase and protein kinase C. 1587 12

Transient receptor potential canonical 1 (TRPC1) is a transmembrane protein expressed in a range of vertebrate cells including smooth muscle, endothelium, neurones and salivary gland cells. It functions as an element of a mixed cationic Ca(2+)-permeable channel, probably commonly as part of a heterotetrameric assembly involving other related proteins such as TRPC5. Wide-ranging biological roles of TRPC1 are suggested, including regulation of smooth muscle and stem cell proliferation, endothelin-evoked arterial contraction, salivary gland secretion, endothelial permeability, glutamatergic neurotransmission, growth cone turning, neuroprotection, neuronal differentiation, lipid raft integrity and the nuclear factor of activated T-cell transcription factor. The mechanisms by which TRPC1 serves these functions are starting to emerge. At one level, it is apparent that TRPC1 is subcellularly compartmentalised, at least in part in cholesterol-rich caveolae closely associated with sub-plasmalemmal endoplasmic reticulum. At another level, TRPC1 is embedded in a protein complex that can include inositol trisphosphate receptor, homer, calmodulin, caveolin-1, FKBP25, I-mfa, MxA, GluR1alpha, bFGFR-1, G(q/11) protein, phospholipase C-beta/gamma, protein kinase C-alpha and RhoA. It is also apparent that TRPC1 responds to general stimuli-not only depletion of intracellular Ca(2+) stores, but also receptor activation, and membrane stretch. We are at the early stages of understanding of how these various signals and components integrate to form a functional channel, and this article provides a brief overview of current progress.
...
PMID:TRPC1: store-operated channel and more. 1596 6

Adhesion of rat glomerular epithelial cells (GEC) to collagen activates focal adhesion kinase (FAK) and the Ras-extracellular signal-regulated kinase (ERK) pathway and supports survival (prevents apoptosis). The present study addresses the relationship between actin organization and the survival phenotype. Parental GEC (adherent to collagen) and GEC stably transfected with constitutively active mutants of mitogen-activated protein kinase kinase (R4F-MEK) or FAK (CD2-FAK) (on plastic) showed ERK activation, low levels of apoptosis, and a cortical distribution of F-actin. Parental GEC adherent to plastic showed increased apoptosis, disorganization of cortical F-actin, and formation of prominent stress fibers. Assembly of cortical F-actin was, at least in part, mediated via ERK. However, disruption of the actin cytoskeleton with cytochalasin D or latrunculin B in parental GEC (on collagen) and in GEC that express R4F-MEK or CD2-FAK (on plastic) decreased ERK activation and increased apoptosis. Expression of a constitutively active RhoA (L(63)RhoA) induced assembly of cortical F-actin, promoted ERK activation, and supplanted the requirement of collagen for survival. Adhesion of GEC to collagen increased phosphatidylinositol-4,5-bisphosphate (PIP(2)). Downregulation or sequestration of PIP(2) by transfection with an inositol 5'-phosphatase or the plextrin-homology domain of phospholipase C-delta1 decreased F-actin content and survival. Moreover, overexpression of wild-type or K256E mutant alpha-actinin-4 with increased affinity for F-actin increased apoptosis. These results demonstrate a reciprocal relationship between collagen-induced cortical F-actin assembly and collagen-dependent survival signaling, including ERK activation. Appropriate remodeling of the actin cytoskeleton may be necessary for facilitating survival, as both disassembly and excessive crosslinking affect survival adversely.
...
PMID:Actin cytoskeleton regulates extracellular matrix-dependent survival signals in glomerular epithelial cells. 1601 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---