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)

Guanylate cyclase was activated 3- to 10-fold by hemin in a dose-dependent manner in membranes prepared from homogenates of rat lung, C6 rat glioma cells, or B103 rat neuroblastoma cells. Maximum activation was observed with 50 to 100 microM hemin with higher concentrations being inhibitory. Activation was observed when Mg2+-GTP but not when Mn2+-GTP was used as the substrate. Increased enzyme activity reflected selective activation of the particulate form of guanylate cyclase; hemin inhibited the soluble form of guanylate cyclase 70 to 90% over a wide range of concentrations. Activation was not secondary to proteolysis since a variety of protease inhibitors failed to alter stimulation by hemin. Protophorphyrin IX had little effect on particulate guanylate cyclase activity and sodium borohydride almost completely abolished hemin-dependent activation. These data suggest a requirement for the ferric form of the porphyrin-metal chelate for activation. However, agents which interact with the iron nucleus of porphyrins, such as cyanide, had little effect on the ability of hemin to activate guanylate cyclase. The stimulatory effects of hemin were observed in the presence of detergents such as Lubrol-PX, and highly purified particulate enzyme could be activated to the same extent as enzyme in native membranes. These data suggest that the interaction of porphyrins with particulate guanylate cyclase is complex in nature and different from that with the soluble enzyme.
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PMID:Selective activation of particulate guanylate cyclase by a specific class of porphyrins. 614 94

Alterations of the chemical structure of protoporphyrin IX markedly altered the activation of soluble guanylate cyclase purified from bovine lung. Hydrophobic side chains at positions 2 and 4 and vicinal propionic acid residues at positions 6 and 7 of the porphyrin ring (protoporphyrin IX, mesoporphyrin IX) were essential for maximal enzyme activation (Ka = 7-8 nM; Vmax = 6-8 mumol of cGMP/min/mg). Substitution of hydrophobic with polar groups (hematoporphyrin IX, coproporphyrin III), or with hydrogen atoms ( deuteroporphyrin IX), and methylation of propionate residues resulted in decreased enzyme stimulation. Stimulatory porphyrins increased the Vmax and the apparent affinities of enzyme for MgGTP and uncomplexed Mg2+. An open central core in the porphyrin ring was essential for enzyme activation. The pyrrolic nitrogen adduct, N-phenylprotoporphyrin IX, was inhibitory and competitive with protoporphyrin IX (KI = 73 nM). Similarly, metalloporphyrins inhibited enzymatic activity and ferro-protoporphyrin IX (KI = 350 nM), zinc-protoporphyrin IX (KI = 50 nM) and manganese-protoporphyrin IX (KI = 9 nM) were competitive with protoporphyrin IX. Inhibitory porphyrins and metalloporphyrins also prevented enzyme activation by S-nitroso-N- acetylpenicillamine and NO. Guanylate cyclase reconstituted with such porphyrins required higher concentrations of protoporphyrin IX for further activation and were not activated by NO. Thus, porphyrins, metalloporphyrins, and NO appeared to interact at a common binding site on guanylate cyclase. This common site is likely that which normally binds heme and, therefore, NO-heme when the heme-containing enzyme is exposed to NO. Thus, NO and nitroso compounds may react with enzyme-bound heme to generate a modified porphyrin which structurally resembles protoporphyrin IX in its interaction with guanylate cyclase.
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PMID:Regulation of soluble guanylate cyclase activity by porphyrins and metalloporphyrins. 614 76

Addition of cGMP to cytosol of human endometrium or to cells of the endometrial cancer line HEC-1 produced severalfold increases in specific estrogen binding (EB) levels. This effect was maximal with 1 microM cGMP in the presence of 0.1 mM isobutylmethylxanthine (a phosphodiesterase inhibitor) during incubations with [3H]estradiol. In contrast, cAMP decreased EB levels under similar conditions. The effects of cyclic nucleotides on EB levels were complete in less than 15 min in the presence of Mg2+, Mn2+, or Ca2+. The EB sites generated by the addition of cGMP during labeling of cytosol with 10 nM [3H]estradiol were found to sediment in the 8S and 4S regions of low-salt glycerol gradients. No changes in EB levels were observed when cyclic nucleotides were added to cytosol depleted of ATP by preincubation at 4 degrees C for 3 hr, but responsiveness was restored by addition of exogenous ATP. The ATP requirement and the pattern of dependence of cyclic nucleotide actions on divalent cation concentrations suggest that cGMP and cAMP effects may be mediated by kinases and may involve phosphorylations. Another possibility is that the cyclic nucleotides interact allosterically with the binder in the presence of ATP. Addition of sodium molybdate, ATP, and GTP to homogenates of endometrial tissue or HEC-1 cells produces increases in EB levels similar to those obtained by the addition of cGMP. However, these compounds are much less active when added to cytoplasm or cytosol. On the basis of these and other observations, it is hypothesized that molybdate, ATP, and GTP affect EB levels primarily by increasing cGMP concentrations through processes involving a plasma membrane-bound guanylate cyclase.
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PMID:Rapid changes in specific estrogen binding elicited by cGMP or cAMP in cytosol from human endometrial cells. 630 87

Excised inside-out patches of vertebrate rod outer segment can support phototransduction. I have examined how ionic and metabolic conditions influence the functional properties of light-sensitive patches from Gekko gekko. I find that such patches retain a variable level of basal phosphodiesterase activity, which lowers the cyclic guanosine monophosphate (cGMP) concentration reaching the channels and reduces the dark current. The dose/response relationship for channel opening by cGMP varies among patches and this variability is only reduced by working in darkness with the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX), suggesting that it is only partially due to phosphodiesterase activity. MgATP or MgGTP, but not Mg or ATP separately, increase this activity but a kinase does not appear to be involved. Intracellular monovalent cations also influence dark current intensity and light response kinetics. With 5 mM MgGTP, 1 mM IBMX, and 144 mM Li+, Na+, K+, or Rb+, dark current intensity and recovery time follow the respective sequences K+ > Rb+ > Na+ > Li+ and K+ < Rb+ < Li+ < Na+. Without IBMX, a dark current develops with K+ but not with Na+. These effects are not due to altered channel permeability (P) [PLi+:Na+:K+:Rb+:guanidinium)/PNa+ = 0.84:1.00:1.01:1.09:0.42], or differential Mg2+ block, but to modulation of guanylate cyclase, which overcomes phosphodiesterase when the major cation is K+ but not when it is Na+.
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PMID:Modulation of guanylate cyclase and phosphodiesterase by monovalent cations and nucleoside triphosphates in light-sensitive excised patches of rod outer segments. 752 3

The N-methyl-D-aspartate (NMDA) receptor plays a key role in synaptic plasticity and is thought to underlie memory, learning and development of the nervous system. The NMDA receptor is a ligand-gated ion channel complex that contains distinct recognition sites for endogenous and exogenous ligands, including glutamate, glycine, Mg2+, Zn2+ and noncompetitive blockers such as MK-801. In the central nervous system, nitric oxide (NO) is produced in some neurons following activation of excitatory amino acids receptors, particularly those of the NMDA receptor. Nitric oxide is synthesized from a L-arginine by the cytoplasmic enzyme nitric oxide synthase (NOS) which is a calcium dependent enzyme, and this pathway is inhibited by the analogues of L-arginine such as NG-monomethyl-L-arginine (L-NMMA) and is augmented by NMDA receptor activation. Activation of the NMDA receptor results in the elevation of intracellular calcium ([Ca2+]i) which in turn activates NOS via the calcium-calmodulin complex. Nitric oxide is not a classical neurotransmitter in the central nervous system since it is not released by exocytosis and does not interact with a receptor protein but rather diffuses rapidly across the membrane and binds with the iron in heme-containing proteins. Nitric oxide can serve as both an oxidizing and reducing agent. It has strong affinity for heme proteins such as guanylyl cyclase, but there is evident that NO may have a regulatory role by oxidizing sulfhydryl groups of non-heme proteins such as those on the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The generation of nitric oxide and its roles in neurotransmission and neurotoxicity. 754 46

Atrial natriuretic factor causes a strong stimulation of human neutrophil migration in the concentration range of 4 x 10(-9) and 10(-7) M. The effect, which depends on the presence of extracellular Mg2+ but not on extracellular Ca2+, is composed of a chemokinetic and a chemotactic component. Cyclic GMP level of neutrophils is enhanced by atrial natriuretic factor. Two inhibitors of soluble guanylate cyclase, 6-anilino-5,8-quinolinedione (LY 83583) and methylene blue, have no effect on stimulation of migration by atrial natriuretic factor. Atrial natriuretic factor-activated migration is inhibited by pertussis toxin. Migration by electroporated neutrophils is synergistically enhanced by guanosine-5'-[gamma thio]triphosphate (GTP gamma[S]) and atrial natriuretic factor or by GTP gamma[S] and chemotactic peptide, while GTP gamma[S] and dioctanoyl glycerol give an additive effect. The results suggest that besides a modulation via cGMP a part of the effect of atrial natriuretic factor on migration is regulated via the ANF receptor-subtype that does not activate guanylate cyclase.
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PMID:Atrial natriuretic factor stimulates migration by human neutrophils. 777 77

An endogenous inhibitor of soluble guanylyl cyclase from bovine lung has been partially purified by use of anion exchange, hydrophobic interaction, and gel filtration chromatography. This inhibitor is a protein with a molecular weight of about 149,000 which was estimated from its elution behavior, versus that of a series of standards, on a Sephacryl S-300-HR column. Its activity was measured by comparison of the level of cGMP production from soluble guanylyl cyclase in the presence and absence of the inhibitor protein. Soluble guanylyl cyclase is inhibited by this protein when either Mg2+ or Mn2+ is used as a cofactor. The insensitivity of its inhibitory activity to both isobutylmethylxanthine and the presence of cGMP demonstrates that this new protein is not a phosphodiesterase. This new protein inhibits both activated and unactivated soluble guanylyl cyclase. Because the inhibition was found to be noncompetitive with respect to the substrate, GTP, it appears that this inhibitor may be an allosteric regulator of soluble guanylyl cyclase.
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PMID:Identification and partial purification of an endogenous inhibitor of soluble guanylyl cyclase from bovine lung. 791 Aug 26

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 role of intracellular signal transduction mechanisms in regulating the motility and metabolism of rat spermatozoa in undiluted caudal epididymal fluid (CEF) was examined. Samples of CEF containing immotile spermatozoa were exposed to drugs and other agents that either stimulate signal transduction pathways or mimic the action of their second messengers. Under these conditions, sperm motility in 25-30 nl of CEF was stimulated by calcium ions (Ca2+), N2,2'-O-dibutyrylguanosine 3':5'-cyclic monophosphate (dibutyryl cGMP), cyclic adenosine 3':5'-monophosphate (cAMP), N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dibutyryl cAMP), 8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo cAMP), caffeine, theophylline and bicarbonate ions (HCO3-). Other agents such as magnesium ions (Mg2+), veratridine, phospholipase C (PLC), ionophore A23187, 1,2-dioctenoyl-sn-glycerol (DAG), phorbol 12-myristate 13-acetate, phospholipase A2 (PLA2), arachidonic acid, and melittin did not significantly influence motility. In the presence of radiolabelled energy substrates, untreated (immotile) spermatozoa in samples of CEF utilised D-[U-14C]glucose and [1-14C]acetate as exogenous energy sources for oxidative metabolism. No detectable 14C-lactate was produced, and none of the drugs altered the rate of glycolytic or oxidative metabolism. The findings suggest that the motility of rat caudal epididymal spermatozoa is regulated by Ca2+ and the guanylate cyclase and adenylate cyclase pathways, but not through the PLC and PLA2 pathways. Also, their metabolism of exogenous substrate was uncoupled from the induction of motility, and their oxidative capacity exceeded the rate of flux of glucose-carbon through the glycolytic pathway.
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PMID:Intracellular signal transduction mechanisms of rat epididymal spermatozoa and their relationship to motility and metabolism. 804 68

We have observed different ATP interactions in two guanylate cyclase (GC)-coupled natriuretic peptide (NP) receptor subtypes, designated NPR-A and NPR-B. The NPR-A is selectively expressed by LLC-PK1 epithelial cells and the NPR-B by NIH-3T3 fibroblast cells. In LLC-PK1 membranes, ATP-Mg2+ potentiated ANP-stimulated GC activity (ANP-s-GC). In contrast, in NIH-3T3 membranes, ATP-Mg2+ inhibited ANP-s-GC but enhanced CNP-stimulated GC activity (CNP-s GC). ATP in the presence of Mn2+ inhibited LLC-PK1 and NIH-3T3 membrane ANP-s-GC and CNP-s-GC. These are the first data suggesting that the ATP-Mg2+ produces different effects between membrane NPR-A and -B subtypes. We have also demonstrated that GC of NPR-B is sensitive to methylene blue.
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PMID:Different ATP effects on natriuretic peptide receptor subtypes in LLC-PK1 and NIH-3T3 cells. 810 67


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