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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

cGMP and Ca2+ are intracellular messengers in vertebrate rod photoreceptors. cGMP is the excitatory messenger, while intracellular free Ca2+ has been implied to be (one of) the messenger(s) in the process of light adaptation in vertebrate rod photoreceptors. The enzyme guanylyl cyclase (GC, EC 4.6.1.2.) catalyzes the reaction GTP-->cGMP + PPi. Bovine retinal rod outer segments (ROS) contain a particulate GC which is inhibited by an increase in free Ca2+ in the submicromolar range, although the precise molecular mechanism underlying this inhibition is unclear. We have developed an optical enzyme-coupled assay to study regulation of the particulate GC endogenous to bovine ROS. The particulate GC exhibited a Ca(2+)-inhibited (IC50 83-144 nM) activity of 13-23 nmol of PPi/(min-(mg of rhodopsin)). ATP increased the maximal velocity of GC by about 2-fold, and this increase was inhibited by the specific PKC inhibitors chelerythrine and the pseudosubstrate-based peptide inhibitor PKC R10-31N. When the factor that mediated the ATP-dependent increase in GC rate was removed by washing, the ATP-dependent increase in GC rate could be reestablished by addition of purified, constitutively active PKC.
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PMID:Activation by PKC of the Ca(2+)-sensitive guanylyl cyclase in bovine retinal rod outer segments measured with an optical assay. 771 73

Using whole-cell voltage-clamp recording of rat osteoblastic cells, we show that PTH-(1-34), known to stimulate protein kinase C (PKC) and adenylate cyclase, has a dual effect on the L-type calcium current. It induces a long-lasting increase and a superimposed reversible decrease, which can be separated by repeating hormone applications. The stimulatory effect is the only effect induced by the (3-34) fragment, able to stimulate PKC but unable to stimulate adenylate cyclase. The L current is stimulated by an active phorbol ester and is reduced by permeable analogues of cyclic AMP. Thus, the effect of PTH-(1-34) can be explained by the opposite effects of PKC and cyclic AMP. Dibutyryl cyclic GMP reduces the L current even more potently than dibutyryl cyclic AMP. The above modulations are all voltage-insensitive. These results led us to reinvestigate the effects of some vitamin D3 metabolites known to stimulate PKC and/or guanylate cyclase, and previously reported to affect the voltage-sensitivity of the L current. We only detected voltage-insensitive effects.
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PMID:Dual modulation of the L-type calcium current of rat osteoblastic cells by parathyroid hormone: opposite effects of protein kinase C and cyclic nucleotides. 785 68

Previous studies from this laboratory have shown that in cultured rat mesangial cells (MC), angiotensin II (ANG II) mediates its effects via activation of phosphatidylinositol-specific phospholipase C (PI-PLC) and phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D (PC-PLD). In addition, guanosine 3',5'-cyclic monophosphate (cGMP)-elevating maneuvers that stimulate particulate and soluble guanylate cyclase [atrial natriuretic factor (ANF) and sodium nitroprusside (SNP), respectively] antagonize ANG II-mediated PI-PLC activation. The current study explored whether cGMP impairs ANG II-mediated PC-PLC and PLD activity. The ANG II-stimulated release of the water-soluble metabolites of PC breakdown (phosphorylcholine and choline) was blocked by ANF and SNP. ANG II-stimulated phosphatidic acid and phosphatidylethanol formation were significantly reduced by ANF and SNP, confirming that cGMP blunted PLD activity. The inhibitory effect of cGMP on PLD could be reversed by N-(2-[methylamino]ethyl)-5-isoquinolinesulfonamide, a blocker of cGMP-dependent protein kinase. In parallel experiments, ANF and SNP abrogated sustained diacylglycerol (DAG) accumulation derived from ANG II stimulation of PC hydrolysis, confirming that cGMP diminished PC-PLC activity. Inhibition of PC-derived DAG accumulation by cGMP was associated with a concomitant decrement in ANG II-mediated translocation of protein kinase C (PKC) activity from the cytosol to the membrane. In summary, in MC, cGMP antagonizes ANG II-mediated PC hydrolysis, DAG formation, and PKC activation. We propose that cGMP-mediated inhibition of phospholipid metabolism and PKC translocation plays an important role in MC vasorelaxation.
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PMID:cGMP antagonizes angiotensin-mediated phosphatidylcholine hydrolysis and C kinase activation in mesangial cells. 786 76

We examined adenosine 5'-triphosphate (ATP), pertussis toxin (PT) and phorbol myristate acetate (PMA), a protein kinase C (PKC) activator, modulation of atrial natriuretic peptide (ANP)-stimulated cell-membrane guanylate cyclase (ANP-s-GC) activity and ANP stimulation of whole-cell cGMP accumulation (ANP-s-cGMP) in an ANP-receptor-transduction cell model, the human renal cell line (SK-NEP-1). Acute and long-term effects of PMA on PKC isotype activity are different: Acute (20-min) PMA activation of PKC inhibits ANP-s-cGMP and ANP-s-GC; whereas, long-term (36-h) PMA treatment inhibits slightly less by only partially down-regulating PKC activity, the type-III PKC isotype being 36-h resistant. Long-term 10(-7)M PMA treatment of cells neither affected membrane basal GC activity nor ANP-s-GC activity but partially inhibited ATP enhancement of ANP-s-GC. This partial inhibition was completely reversed by the PKC inhibitor H7 and a PKC inhibitory antibody but only partially reversed by the antibody to the catalytic domain of PKC type III. The EC50 for ATP and its non-phosphorylating analog ATP gamma S in the presence of acute PMA inhibition of ANP-s-cGMP was similar (approximately 10(-9)). This enhancement of PMA inhibition was two orders of magnitude more sensitive (EC50 10(-7)M) than inhibition of ANP-s-cGMP that we previously reported for acute PMA treatment of whole SK-NEP-1 cells. The three- to four-fold ATP enhancement of cell membrane ANP-s-GC was not blocked by 12-hour preincubation of cells with 150 ng/mL PT but was completely blocked if 2-x-10(-7)M PMA was then added for 20 minutes, indicating that acute activation of PKC by PMA does not require a functional "G-type" protein. Acute PMA inhibition of ANP-s-cGMP was reversed by permeabilizing SK-NEP-1 cells to a specific PKC inhibitory peptide, further confirming that PMA inhibition was mediated through PKC activation. These data demonstrated that ANP-s-GC and ANP-s-cGMP were modified through non-phosphorylating interactions with ATP, by multiple PMA activatable PKC isoforms, and that neither were affected by PT-sensitive guanine-nucleotide-binding (G)-protein(s).
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PMID:Adenosine 5'-triphosphate, phorbol ester, and pertussis toxin effects on atrial natriuretic peptide stimulation of guanylate cyclase in a human renal cell line. 790 11

Stimulation of guanylyl cyclase A (GC-A) by atrial natriuretic peptide (ANP) is antagonized by activators of protein kinase C (PKC). Thus, it has been suggested that PKC phosphorylates and desensitizes GC-A. Here, we have developed stable GC-A transfectants of NIH3T3 cells, which display marked reductions in hormone-dependent cGMP elevations and guanylyl cyclase activity after incubation with ANP or phorbol 12-myristate 13-acetate (PMA). ANP binding and immunoblot analysis indicated that the decreases were not due to receptor internalization or degradation. GC-A isolated from 32PO4-labeled cells contained phosphoserine and phosphothreonine. ANP and/or PMA addition caused substantial decreases in the 32P content of the receptor that coincided with reductions in hormone-dependent guanylyl cyclase activity. The specific PKC inhibitor, GF-109203X, completely blocked the PMA-dependent dephosphorylation and desensitization of GC-A but failed to inhibit either ANP-dependent process. Tryptic phosphopeptide maps of GC-A isolated from ANP- or PMA-treated cells were unique, suggesting that the sites that dephosphorylated in response to each agent were different. In contrast to previous reports, we conclude that PMA and ANP desensitization of GC-A are distinct events mediated by dephosphorylation of specific residues through PKC-dependent and -independent pathways, respectively.
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PMID:Protein kinase C-dependent desensitization of the atrial natriuretic peptide receptor is mediated by dephosphorylation. 791 Jan 66

Calcium can influence the cGMP/guanylate cyclase system in many tissues, including rat colon. The mechanisms involved in this phenomenon, however, are unclear. To further elucidate the mechanisms involved in the Ca(2+)-induced activation of rat colonic particulate guanylate cyclase, isolated colonocytes were incubated with Ca2+ or other agents, and crude membrane prepared and analyzed for particulate guanylate cyclase activity. Alternatively, the test agents were directly added to the guanylate cyclase reaction mixture containing isolated membranes. The results of these studies demonstrated: (i) extracellular Ca2+ (1 and 2 mM) increased basal particulate guanylate cyclase activity; (ii) increases in intracellular Ca2+ induced by 10 microM thapsigargin activated this enzyme; (iii) preincubation of the cells with 50 nM staurosporine, a broad-spectrum inhibitor of protein kinases, including protein kinase C (PKC), or 5 microM U73122, a specific inhibitor of phosphoinositide-phospholipase C-dependent processes, blocked the Ca(2+)-induced increase in particulate guanylate cyclase activity; (iv) incubation of cells with 1 microM 12-O-tetradecanoyl phorbol 13-acetate (TPA), an activator of PKC, stimulated guanylate cyclase; (v) no additivity in stimulation of this enzyme was observed when cells were concomitantly incubated with 1 microM TPA and 2 mM extracellular Ca2+; (vi) incubation of membranes with 250 nM TPA, in the presence of 0.2 mM Ca2+, 6 mM Mg2+, and 1 mM ATP, activated guanylate cyclase; and (vii) incubation of membranes with purified rat brain PKC further augmented this stimulation. These results indicate that Ca2+ activates rat colonic particulate guanylate cyclase, at least in part, via a PKC-dependent mechanism.
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PMID:Protein kinase C mediates the calcium-induced activation of rat colonic particulate guanylate cyclase. 794 95

The peptide hormone atrial natriuretic factor (ANF) exerts its effect in a receptor-mediated fashion and the membrane-bound form of guanylate cyclase represents a biologically active ANF receptor; thus, cGMP has been considered a second messenger of ANF. To understand the mechanisms of ANF action, we have studied its effect on protein phosphorylation in the plasma membrane preparations of murine Leydig tumor (MA-10) cells, which overexpress guanylate cyclase-coupled ANF receptor molecules in high density. After pretreatment of the plasma membranes with ANF (100 nM), a marked decrease in phosphorylation of the 78-kDa protein kinase C (PKC) and the 240-kDa protein was observed. Phosphorylation of the 78-kDa PKC was also inhibited by cGMP (0.1 mM); however, phosphorylation of the 240-kDa protein was not affected by cGMP. The quantitative analyses, as determined by densitometric scanning, revealed that both ANF and cGMP inhibited phosphorylation of the 78-kDa PKC by approximately 75% and 45%, respectively. The inhibitory effect of ANF on phosphorylation of the 240-kDa protein was almost 90%, but cGMP did not show any discernible effect on its phosphorylation in plasma membranes of MA-10 cells. Phosphorylation of the 78-kDa PKC was stimulated by Ca2+ and phospholipids, and it immunologically cross-reacted with antiserum against brain PKC. Furthermore, in these plasma membrane preparations, the 78-kDa PKC was immunoprecipitated and its phosphorylation was inhibited by ANF. These data provide evidence for a new signal transduction mechanism of ANF that negatively regulates phosphorylation of the 78-kDa PKC and the 240-kDa protein in a cGMP-dependent and -independent manner in Leydig cells.
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PMID:Atrial natriuretic factor inhibits the phosphorylation of protein kinase C in plasma membrane preparations of cultured Leydig tumor cells. 805 32

The endothelial cell has a unique intrinsic feature: it produces a most potent vasopressor peptide hormone, endothelin (ET-1), yet it also contains a signaling system of an equally potent hypotensive hormone, atrial natriuretic factor (ANF). This raises two related curious questions: does the endothelial cell also contain an ET-1 signaling system? If yes, how do the two systems interact with each other? The present investigation was undertaken to determine such a possibility. Bovine pulmonary artery endothelial (BPAE) cells were chosen as a model system. Identity of the ANF receptor guanylate cyclase was probed with a specific polyclonal antibody to the 180 kDa membrane guanylate cyclase (mGC) ANF receptor. A Western-blot analysis of GTP-affinity-purified endothelial cell membrane proteins recognized a 180 kDa band; the same antibody inhibited the ANF-stimulated guanylate cyclase activity; the ANF-dependent rise of cyclic GMP in the intact cells was dose-dependent. By affinity cross-linking technique, a predominant 55 kDa membrane protein band was specifically labeled with [125I]ET-1. ET-1 treatment of the cells showed a migration of the protein kinase C (PKC) activity from cytosol to the plasma membrane; ET-1 inhibited the ANF-dependent production of cyclic GMP in a dose-dependent fashion with an EC50 of 100 nM. This inhibitory effect was duplicated by phorbol 12-myristate 13-acetate (PMA), a known PKC-activator. The EC50 of PMA was 5 nM. A PKC inhibitor, 1-(5-isoquinolinyl-sulfonyl)-2-methyl piperazine (H-7), blocked the PMA-dependent attenuation of ANF-dependent cyclic GMP formation. These results demonstrate that the 180 kDa mGC-coupled ANF and ET-1 signaling systems coexist in endothelial cells and that the ET-1 signal negates the ANF-dependent guanylate cyclase activity and cyclic GMP formation. Furthermore, these results support the paracrine and/or autocrine role of ET-1.
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PMID:Interaction of atrial natriuretic factor and endothelin-1 signals through receptor guanylate cyclase in pulmonary artery endothelial cells. 809 23

Soluble guanylate cyclase was found to be phosphorylated by protein kinase C in intact PC12 pheochromocytoma cells. The phosphate incorporation into guanylate cyclase upon addition of phorbol 12-O-myristate 13-acetate (PMA) to PC12 cells in culture coincided with an increased intracellular cGMP level. A strong correlation between phosphate incorporation into guanylate cyclase and increased cGMP level was also observed by time-course and dose-response studies of the PMA effect, as well as when cells were treated with various phorbol esters and diacylglycerols or with various protein kinase C inhibitors. The cAMP system and the presence of extracellular Ca2+ were found not to be involved in guanylate cyclase phosphorylation. The phosphorylation and activation of guanylate cyclase by protein kinase C represent a possible mechanism whereby agonist-stimulation of receptors coupled to phosphoinositide hydrolysis induces cGMP synthesis.
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PMID:Activation of soluble guanylate cyclase through phosphorylation by protein kinase C in intact PC12 cells. 810 Jul 14

We studied the activation and inactivation of recombinant guanylyl cyclase (GC) C stably expressed in human kidney 293 cells. Activation of GC-C by heat-stable enterotoxin (STa), Cd2+, hemin, or the detergent Triton X-100 was followed by a rapid inactivation of the enzyme. Adenine nucleotides were found to prevent the inactivation process in native membranes, as well as following enzyme solubilization and immunopurification. Inactivation of GC-C was not associated with dephosphorylation. However, the phosphorylation of GC-C was promoted by phorbol esters, known activators of protein kinase C. The activation of purified GC-C by STa required the presence of a nonspecific factor as exemplified by bovine serum albumin. When immunopurified GC-C, stabilized by ATP and bovine serum albumin, was analyzed by SDS-polyacrylamide gel electrophoresis under nonreducing conditions, proteins with almost twice the molecular mass (220 and 245 kDa) of the monomer were observed. The mobility of these high M(r) GC-C forms was reduced by STa, suggesting that STa induces a conformation change in a preexisting GC-C dimer. These results indicate that ATP interacts directly with GC-C, stabilizing its active conformation and that the activation of GC-C may occur in the absence of other specific regulatory factors.
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PMID:Heat-stable enterotoxin activation of immunopurified guanylyl cyclase C. Modulation by adenine nucleotides. 810 20


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