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

Studies were undertaken to determine whether PTH-related protein (PTHrP) (107-139) mobilizes [Ca(2+)](i) in osteoblastic osteosarcoma UMR 106 cells. PTHrP (107-139), in a manner similar to PTHrP (107-111), induced a rapid [Ca(2+)](i) response in these cells that was dose dependent (EC(50) of approximately 0.1 pM) and more efficient than that of PTHrP (1-36) (EC(50) of approximately 1 nM). This effect of PTHrP (107-139) was abrogated by micromolar doses of verapamil or nifedipine. However, it was unaffected by 10 microM U73122 (a phospholipase C inhibitor), 100 microg/ml heparin (an inositol 1,4,5-trisphosphate receptor inhibitor), or 400 ng/ml pertussis toxin (a G(i) inhibitor), which inhibited the [Ca(2+)](i) response to PTHrP (1-36), or by either 25 nM bisindolylmaleimide I (BIM), a protein kinase (PK) C inhibitor, or 1 microM phorbol-12-myristate-13-acetate preincubation (22 h). PTHrP (107-139) and PTHrP (1-36), at 100 nM, desensitized the [Ca(2+)](i) response to a second challenge with the same peptide, but not with the other peptide in these cells. PTHrP (7-34), a type 1 PTH/PTHrP receptor (PTH1R) antagonist, decreased the effect of PTHrP (1-36) on [Ca(2+)](i). In contrast, PTHrP (107-111), but neither PTHrP (109-138) nor PTHrP (7-34), abolished this effect of PTHrP (107-139). Both PTHrP (107-139) and PTHrP (1-36), added together at submaximal doses, induced a higher [Ca(2+)](i) response. Moreover, PTHrP (107-139) increased the efficacy of PTHrP (1-36) on [Ca(2+)](i), but decreased its induced increase in PKA activity in these cells. Verapamil or nifedipine (at 50 microM) or 25 nM BIM, but not 25 microM adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer, a PKA inhibitor, abolished the PTHrP (107-139)-induced increase in interleukin 6 messenger RNA (assessed by RT, followed by PCR) in UMR 106 cells. This peptide also increased c-fos messenger RNA in these cells; an effect inhibited by BIM, but unaffected by either verapamil or EGTA. These findings support the existence of high-affinity receptors for PTHrP (107-139), associated with an induced Ca(2+) influx, different from the PTH1R in UMR 106 cells. The present results suggest that PTHrP could affect bone turnover by interacting with the PTH1R and other yet unknown receptors in bone cells through complex mechanisms.
 ...
PMID:C-terminal parathyroid hormone-related protein (PTHrP) (107-139) stimulates intracellular Ca(2+) through a receptor different from the type 1 PTH/PTHrP receptor in osteoblastic osteosarcoma UMR 106 cells. 1141 93

The prostacyclin receptor (IP) is primarily coupled to G alpha(s)-dependent activation of adenylyl cyclase; however, a number of studies indicate that the IP may couple to other secondary effector systems perhaps in a species-specific manner. In the current study, we investigated the specificity of G protein:effector coupling by the mouse (m) IP overexpressed in human embryonic kidney 293 cells and endogenously expressed in murine erythroleukemia cells. The mIP exhibited efficient G alpha(s) coupling and concentration-dependent increases in cAMP generation in response to the IP agonist cicaprost; however, mIP also coupled to G alpha(i) decreasing the levels of cAMP in forskolin-treated cells. mIP coupling to G alpha(i) was pertussis toxin-sensitive and was dependent on protein kinase (PK) A activation status. In addition, the mIP coupled to phospholipase C (PLC) activation in a pertussis toxin-insensitive, G alpha(i)-, G beta gamma-, and PKC-independent but in a G alpha(q)- and PKA-dependent manner. Whole cell phosphorylation assays demonstrated that the mIP undergoes cicaprost-induced PKA phosphorylation. mIP(S357A), a site-directed mutant of mIP, efficiently coupled to G alpha(s) but failed to couple to G alpha(i) or to efficiently couple to G alpha(q):PLC. Moreover, mIP(S357A) did not undergo cicaprost-induced phosphorylation confirming that Ser(357) is the target residue for PKA-dependent phosphorylation. Finally, co-precipitation experiments permitted the detection of G alpha(s), G alpha(i), and G alpha(q) in the immunoprecipitates of mIP, whereas only G alpha(s) was co-precipitated with mIP(S357A) indicating that Ser(357) of mIP is essential for G alpha(i) and G alpha(q) interaction. Moreover, inhibition of PKA blocked co-precipitation of mIP with G alpha(i) or G alpha(q). Taken together our data indicate that the mIP, in addition to coupling to G alpha(s), couples to G alpha(i) and G alpha(q); however, G alpha(i) and G alpha(q) coupling is dependent on initial cicaprost-induced mIP:G alpha(s) coupling and phosphorylation of mIP by cAMP-dependent PKA where Ser(357) was identified as the target residue for PKA phosphorylation.
 ...
PMID:Protein kinase A-mediated phosphorylation of serine 357 of the mouse prostacyclin receptor regulates its coupling to G(s)-, to G(i)-, and to G(q)-coupled effector signaling. 3000 85

Growth plate chondrocyte function is modulated by the vitamin D metabolite 1alpha,25-(OH)(2)D(3) via activation of protein kinase C (PKC). In previous studies with cells derived from prehypertrophic and upper hypertrophic zones of rat costochondral cartilage (growth zone cells), inhibition of prostaglandin production with indomethacin caused a decrease in the stimulation of PKC activity, suggesting that changes in prostaglandin levels mediate the 1alpha,25-(OH)(2)D(3)-dependent response in these cells. Growth zone cells also respond to PGE(2) directly, indicating that prostaglandins act as autocrine or paracrine regulators of chondrocyte metabolism in the growth plate. The aim of the present study was to identify which PGE(2) receptor subtypes (EP) mediate the effects of PGE(2) on growth zone cells. Using primers specific for EP1-EP4, reverse transcription-polymerase chain reaction (RT-PCR) amplified EP1 and EP2 cDNA in a RT-dependent manner. In parallel experiments, we used EP subtype-specific agonists to examine the role of EP receptors in 1alpha,25-(OH)(2)D(3)-mediated cell proliferation and differentiation. 17-Phenyl-trinor-PGE(2) (PTPGE(2)), an EP1 agonist, decreased [3H]-thymidine incorporation in a dose-dependent manner and augmented the 1alpha,25-(OH)(2)D(2)-induced inhibition of [3H]-thymidine incorporation. PTPGE(2) also caused significant increases in proteoglycan production, as measured by [35S]-sulfate incorporation, and alkaline phosphatase specific activity. 1alpha,25-(OH)(2)D(3)-induced alkaline phosphatase activity was only slightly stimulated by PTPGE(2). In contrast, 1alpha,25-(OH)(2)D(3)-induced PKC activity was synergistically increased by PTPGE(2), whereas EP1 antagonists SC-19220 and AH6809 inhibited PKC activity in a dose-dependent manner. The EP2, EP3 and EP4 agonists had no effect on the various cell-induced responses measured. EP1 receptor-induced responses were blocked by the phospholipase C inhibitor U73122, and reduced by PKA inhibitors. EP1 receptor-induced PKC activity was insensitive to pertussis toxin or choleratoxin but blocked by the G-protein inhibitor GDPbetaS, suggesting the involvement of G(q). These results suggest that the EP1 receptor subtype mediates various PGE(2)-induced cellular responses in growth zone chondrocytes leading to decreased proliferation and enhanced differentiation, as well as the effect of 1alpha,25-(OH)(2)D(3) on cellular maturation.
 ...
PMID:Characterization of PGE(2) receptors (EP) and their role as mediators of 1alpha,25-(OH)(2)D(3) effects on growth zone chondrocytes. 1159 7

A full biphasic insulin response is the most sensitive index for well-coupled beta-cell signal transduction. While first-phase insulin response is extremely sensitive to potentiating and inhibiting modulations, full expression of second-phase response requires near maximally activated beta-cell fuel metabolism. In the isolated rat pancreas, accelerated calcium entry or activation of protein kinase (PK)-A or PKC result in no insulin response in the absence of fuel metabolism. At submaximal levels of beta-cell fuel secretagogue, arginine (which promotes calcium entry) or glucagon (which activates PKA) produces a small first-phase insulin response but minimal or no second-phase response; carbachol (which activates PKC and promotes calcium entry) generates biphasic insulin response in the presence of minimal fuel (3.3 mmol/l glucose). Glucagon produces full biphasic response in the presence of 10.0 mmol/l glucose, whereas arginine requires near-maximal stimulatory glucose (16.7 mmol) to produce full biphasic insulin response. Thus, PKA and PKC signal pathways potentiate primary signals generated by fuel secretagogues to induce full biphasic insulin response, while calcium recruitment alone is insufficient to potentiate primary signals generated at low levels of fuel secretagogue. We suggest that three families of PKs (calmodulin-dependent PK [CaMK], PKA, and PKC) function as distal amplifiers for stimulus-secretion coupling signals originating from fuel metabolism, as well as from incretins acting through membrane receptors, adenylate cyclase, and phospholipase C. Several isoenzymes of PKA and PKC are present in pancreatic beta-cells, but the specific function of most is still undefined. Each PK isoenzyme is activated and subsequently phosphorylates its specific effector protein by binding to a highly specific anchoring protein. Some diabetes-related beta-cell derangements may be linked to abnormal function of one or more PK isoenzymes. Identification and characterization of the specific function of the individual PK isoenzymes may provide the tool to improve the insulin response of the diabetic patient.
 ...
PMID:Beta-cell protein kinases and the dynamics of the insulin response to glucose. 1181 61

We have previously shown (Otani et al., 1999b) that bath application of (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV), the agonist of group II metabotropic glutamate receptors (mGluRs), induces postsynaptic Ca2+-dependent long-term depression (LTD) of layer I-II to layer V pyramidal neuron glutamatergic synapses of rat medial prefrontal cortex. In the present study, we examined detailed mechanisms of this DCG IV-induced LTD. First, the group II mGluR antagonist (RS)-alpha-methylserine-O-phosphate monophenyl ester blocked DCG IV-induced LTD, and another group II agonist (2S,3S,4S)-CCG/(2S,1'S,2'S)-2-(carboxycyclopropyl)glycine-induced LTD, suggesting that LTD is indeed mediated by the activation of group II mGluRs. Second, DCG IV-induced LTD was blocked by the NMDA receptor antagonist AP-5, whereas DCG IV did not potentiate NMDA receptor-mediated synaptic responses. Interruption of single test stimuli during DCG IV application blocked DCG IV-induced LTD. These results suggest that small NMDA receptor-mediated responses evoked by single synaptic stimuli contribute to DCG IV-induced LTD. Third, DCG IV-induced LTD was blocked or reduced by the following drugs: phospholipase C inhibitor U-73122 (bath-applied or postsynaptically injected), postsynaptically injected IP3 receptor blocker heparin, phospholipase D-linked mGluR blocker PCCG-13, PKC inhibitor RO318220, postsynaptically injected PKC inhibitor PKC(19-36), and PKA inhibitor KT-5720. Fourth, fluorescent Ca2+ analysis techniques revealed that DCG IV increases Ca2+ concentration in prefrontal layer V pyramidal neurons. These Ca2+ rises and the LTD were both blocked by postsynaptic heparin in the same cells. Taken together, these results suggest that postsynaptic group II mGluRs, linked to phospholipase C and probably also phospholipase D, induce LTD through postsynaptic PKC activation and IP3 receptor-mediated postsynaptic increases of Ca2+ concentration.
 ...
PMID:Long-term depression induced by postsynaptic group II metabotropic glutamate receptors linked to phospholipase C and intracellular calcium rises in rat prefrontal cortex. 1197 20

Parathyroid hormone (PTH) is a major regulator of osteoclast formation and activation, effects that are associated with reciprocal up- and down-regulation of RANKL and osteoprotegerin (OPG), respectively. The roles of specific downstream signals generated by the activated PTH/PTH-related protein (PTHrP) receptor (PTH1R), such as cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) and phospholipase C/protein kinase C (PLC/PKC), in controlling RANKL and OPG expression and osteoclastogenesis remain uncertain. In MS1 conditionally transformed clonal murine marrow stromal cells, which support PTH-induced osteoclast formation from cocultured normal spleen cells, PTH(1-34) increased RANKL and macrophage colony-stimulating factor (M-CSF) mRNA expression and decreased that of OPG when present continuously for 7-20 days at 37 degrees C in the presence of dexamethasone (Dex). In cells precultured for 7 days and then treated with PTH(1-34), similar reciprocal regulation of RANKL and OPG occurred, maximally at 6-24 h, that was of greater amplitude than the changes induced by chronic (7-10 days) PTH exposure. These acute effects of PTH(1-34) were mimicked by PKA stimulators (8-bromoadenosine [8Br]-cAMP or forskolin [FSK]), blocked by the PKA inhibitor Rp-cAMPs but unaffected by the PKC inhibitor GF109203X. Amino-truncated PTH(1-34) analogs PTH(5-34) and PTH(7-34) neither increased cAMP production in MS1 cells nor regulated RANKL or OPG mRNA. Reciprocal RANKL/OPG mRNA regulation was induced in MS1 cells by PTH(3-34) but only at high concentrations that also increased cAMP. The highly PKA-selective PTH analog [Gly1,Arg19]human PTH(1-28) exerted effects similar to PTH(1-34) on RANKL and OPG mRNAs and on osteoclast formation, both in MS1/spleen cell cocultures and in normal murine bone marrow cultures. The direct PKC stimulator 12-O-tetradecanoylphorbol-13-acetate (PMA) did not induce RANKL mRNA in MS1 cells, but it did up-regulate OPG mRNA and also antagonized osteoclast formation induced by PTH(1-34) in both MS1/spleen cocultures and normal bone marrow cultures. Thus, cAMP/PKA signaling via the PTH1R is the primary mechanism for controlling RANKL-dependent osteoclastogenesis, although direct PKC activation may negatively regulate this effect of PTH by inducing expression of OPG.
 ...
PMID:Cyclic adenosine monophosphate/protein kinase A mediates parathyroid hormone/parathyroid hormone-related protein receptor regulation of osteoclastogenesis and expression of RANKL and osteoprotegerin mRNAs by marrow stromal cells. 1221 38

Signalling cascades involved in chemokine production by human phagocytes following infection with Mycobacterium tuberculosis are still not defined. We used specific pharmacologic inhibitors to identify the signalling molecules which lead to interleukin (IL)-8 and MCP-1 production in human monocytes in response to M. tuberculosis infection. Inhibition of extracellular signal-regulated (ERK) or p38 mitogen-activated protein kinase by PD98059 and SB203580 respectively, significantly affected chemokine production. However, only the presence of both inhibitors completely blocked the release. A down-regulation of chemokine secretion was found in presence of inhibitors of protein kinase (PK)C and phospholipase C. Moreover, production depended on transcription activation via the nuclear factor-kappa B (NF-kappaB), as demonstrated by treatment with actinomycin D and caffeic acid phenethyl ester. In addition, activation of PKA and the phosphoinoside 3-kinase (PI-3k)/p70 ribosomal S6 kinase cascade was required to have maximal MCP-1 but not IL-8 production. In conclusion, this study provides evidence that multiple signal transduction pathways are involved in M. tuberculosis -induced chemokine secretion by human monocytes. Moreover, for the first time this report indicates that inhibitors of some signalling molecules are able to dissociate IL-8 from MCP-1 secretion. Differences in the regulatory pathways of chemokine production can potentially be exploited therapeutically.
 ...
PMID:Pharmacological analysis of signal transduction pathways required for mycobacterium tuberculosis-induced IL-8 and MCP-1 production in human peripheral monocytes. 1239 71

Orexin (ORX)-A is a 33-amino acid peptide with demonstrated roles in the regulation of energy metabolism, autonomic control, and sleep. Orexin receptors (OXRs), OX1R and OX2R, and immunoreactive axons are present in the nucleus tractus solitarius (NTS). We demonstrated previously that bath application of ORX-A depolarizes NTS neurons through activation of a nonselective cationic conductance (NSCC) and inhibition of a sustained potassium current (IK). The present study examined the signaling pathways underlying the excitatory effects of ORX-A on NTS neurons using whole-cell patch-clamp recording techniques. Inclusion of guanosine 5'-O-(2-thiodiphosphate) in the internal pipette solution abolished the effects of ORX-A, confirming that the actions of ORX-A are mediated by G-protein-coupled receptors. The responses of ORX-A were also blocked by a phospholipase C (PLC) inhibitor, D609, and by a nonselective protein kinase (PK) inhibitor, H7, demonstrating the involvement of PLC and protein kinases. However, PKA appears not to play a role, because the depolarizing effects of ORX-A were still observed when the PKA inhibitor peptide (6-22) was included in the pipette solution, and bath application of 8-bromo-cAMP (a PKA agonist) was without effect on NTS neurons. In contrast, 12-O-tetradecanoylphorbol-13-acetate (a PKC agonist) depolarized NTS neurons, and bisindolylmaleimide (BIS), a PKC inhibitor, abolished the depolarizing effects of ORX-A. Finally, voltage-clamp experiments demonstrated that BIS also blocked the activation of NSCC and inhibition of IK by ORX-A in NTS neurons. These results therefore show that the excitatory effects of ORX-A on NTS neurons are mediated through activation of the PLC-PKC-NSCC and -IK signaling pathways, which probably result from OXR-coupled activation of Gq.
 ...
PMID:Excitatory effects of orexin-A on nucleus tractus solitarius neurons are mediated by phospholipase C and protein kinase C. 1286 5

We have previously reported that dopamine (DA) depresses non-NMDA receptor-mediated glutamatergic transmission in the rat parabrachial nucleus (PBN), an interface between brainstem and forebrain that is implicated in autonomic regulation. This work examined cellular signalling pathways that might underlie this DA-induced synaptic depression. Direct activation of adenylyl cyclase with 10 microM forskolin increased the evoked EPSC but did not occlude DA-induced EPSC depression. Similarly, a preferential protein kinase A inhibitor, H-7 (10 microM), did not block DA's synaptic effects. Incubation of slices with cholera toxin (CTX; 1 microgram/ml) or pertussis toxin (PTX; 0.5 microgram/ml) for 20 h, procedures used to irreversibly activate or disable the G(s) and G(i) proteins, respectively, did not change DA's effects. The putative phospholipase C inhibitor, U-73122 (10 microM) and its inactive analogue U-73343 (10 microM) did not alter DA-induced reduction in the EPSCs. Alterations in signalling molecules downstream of phospholipase C including depleting internal calcium stores by thapsigargin and cyclopiazonic acid and blocking protein kinase C with chelerythrine, had no effect on DA-induced synaptic depression. Furthermore, DA's depression of the non-NMDA response was not blocked by APV, an NMDA receptor antagonist. Finally, DA depressed evoked, pharmacologically isolated NMDA receptor-mediated synaptic responses while increasing NMDA-induced inward currents in the PBN. These results indicate that DA-induced synaptic effects in the PBN are not through the activation of cholera or pertussis toxin sensitive G proteins. Furthermore, it does not employ the adenylyl cyclase-cAMP-PKA cascade, the phospholipase C signalling pathway and NMDA receptor-coupled mechanisms to depress excitatory synaptic transmission in the PBN.
 ...
PMID:Dopamine-induced synaptic depression in the parabrachial nucleus is independent of CTX- and PTX-sensitive G-proteins, PKA and PLC signalling pathways. 1467 13

1. Adenosine A(1), A(2A), and A(3) receptors (ARs) and extracellular signal-regulated kinase 1/2 (ERK1/2) play a major role in myocardium protection from ischaemic injury. In this study, we have characterized the adenosine receptor subtypes involved in ERK1/2 activation in newborn rat cardiomyocytes. 2. Adenosine (nonselective agonist), CPA (A(1)), CGS 21680 (A(2A)) or Cl-IB-MECA (A(3)), all increased ERK1/2 phosphorylation in a time- and dose-dependent manner. The combined maximal response of the selective agonists was similar to adenosine alone. Theophylline (nonselective antagonist) inhibited completely adenosine-mediated ERK1/2 activation, whereas a partial inhibition was obtained with DPCPX (A(1)), ZM 241385 (A(2A)), and MRS 1220 (A(3)). 3. PD 98059 (MEK1; ERK kinase inhibitor) abolished all agonist-mediated ERK1/2 phosphorylation. Pertussis toxin (PTX, G(i/o) blocker) inhibited completely CPA- and partially adenosine- and Cl-IB-MECA-induced ERK1/2 activation. Genistein (tyrosine kinase inhibitor) and Ro 318220 (protein kinase C, PKC inhibitor) partially reduced adenosine, CPA and Cl-IB-MECA responses, without any effect on CGS 21680-induced ERK1/2 phosphorylation. H89 (protein kinase A, PKA inhibitor) abolished completely CGS 21680 and partially adenosine and Cl-IB-MECA responses, without any effect on CPA response. 4. Cl-IB-MECA-mediated increases in cAMP accumulation suggest that A(3)AR-induced ERK1/2 phosphorylation involves adenylyl cyclase activation via phospholipase C (PLC) and PKC stimulation. 5. In summary, we have shown that ERK1/2 activation by adenosine in cardiomyocytes results from an additive stimulation of A(1), A(2A), and A(3)ARs, which involves G(i/o) proteins, PKC, and tyrosine kinase for A(1) and A(3)ARs, and Gs and PKA for A(2A)ARs. Moreover, the A(3)AR response also involves a cAMP/PKA pathway via PKC activation.
 ...
PMID:Characterization of ERK1/2 signalling pathways induced by adenosine receptor subtypes in newborn rat cardiomyocytes. 1475 70


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