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)

Our previous characterization of equilibrium binding kinetics of atrial natriuretic peptide (ANP) to the surface of inner medullary collecting duct (IMCD) cells suggested the existence of a single class of high-affinity receptors, functionally coupled to increases in cellular guanosine 3',5'-cyclic monophosphate (cGMP). We have now sought to understand the mode of regulation of this signal transduction system by studying the particulate guanylate cyclase (PGC) enzyme from these cells. PGC activity with and without ANP in membranes, made by homogenization and high-speed centrifugation of suspensions of IMCD cells, was linear up to 5 min and was stimulated by ANP [143 +/- 21 (ANP) vs. 38 +/- 7 (control) pmol/mg protein, n = 3, P less than 0.02]. Vmax increased more than threefold with ANP [130 +/- 19 (ANP) vs. 35 +/- 4 (control) pmol.mg protein-1.min-1, n = 4, P less than 0.005] without significant change in the Km [0.68 +/- 0.17 (ANP) vs. 0.55 +/- 0.08 (control) mM] of the enzyme. Half-maximal stimulation of guanylate cyclase activity occurred at 5 x 10(-10) M ANP, a concentration consistent with our binding data, and with physiological effect. PGC required divalent cations for basal activity and for ANP-stimulated activity; Mg2+ and Mn2+ were most potent in this respect, and Ca2+ was without effect. Both basal and stimulated PGC activities were inhibited in response to changes in the NaCl, but not urea concentration of the assay system. We conclude that binding to the single 120-130 kDa ANP receptor in IMCD cells results in stimulation of PGC by increasing its Vmax and thereby elevating intracellular cGMP, the likely mediator of ANP action in these cells.
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PMID:Characteristics of ANP-sensitive guanylate cyclase in inner medullary collecting duct cells. 256 78

Plasma membranes from bovine tracheal smooth muscle show guanylyl cyclase activity, which can be stimulated by muscarinic agonists such carbamylcholine and oxotremorine and blocked by atropine. This stimulation was observed in the presence of 150 mM NaCl. In the absence of this salt, guanylyl cyclase activity was considerably higher but was not affected by muscarinic agonists. Carbamylcholine decreased the apparent Km but did not change the Vmax of this enzyme. When plasma membrane fractions were extracted with 1% octylglucoside, guanylyl cyclase activity was preserved, however the muscarinic activation was abolished, despite a muscarinic receptor capable of [3H]quinuclidinylbenzilate binding being present in the extract. The detergent extraction changed the affinity of guanylyl cyclase for GTP but the Mn2+ kinetics was unaltered. Based on these findings and on current information in the literature, we propose that another component is required to restore the link between the muscarinic receptor and guanylyl cyclase, however the nature of this component remains to be established.
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PMID:Muscarinic agents modify kinetics properties of membrane-bound guanylyl cyclase activity. 256 12

Two classes of atrial natriuretic peptide (ANP) receptors are present in purified sarcolemmal membrane fractions isolated from rat ventricle. Scatchard analysis using [125I]-ANP reveals high affinity (Kd approximately 10(-11) M) and low affinity (Kd approximately 10(-9) M) binding sites. Basal guanylate cyclase activities associated with these membrane fractions range from 3.2 +/- 1.3 pmol/min/mg protein in the presence of Mg2+ to 129 +/- 17 pmol/min/mg protein in the presence of Mn2+. Millimolar concentrations of adenosine triphosphate (ATP) potentiates Mg2+- but not Mn2+-supported activity. Binding of ANP to the low affinity site but not the high affinity site results in a maximum 2-fold activation of Mn2+- and up to 6-fold activation of Mg2+/ATP supported guanylate cyclase activities.
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PMID:Atrial natriuretic peptide receptors and activation of guanylate cyclase in rat cardiac sarcolemma. 256 65

Activity of guanylate cyclase in rat thrombocytes exceeded the enzymatic activity in heart tissue 3.2- and 6.6-fold, if Mn2+ and Mg2+ were used as cofactors, respectively. Dithiothreitol (DTT) at concentrations 2 x 10(-5) M-2 x 10(-2) M activated guanylate cyclase both in rat heart and thrombocytes, while 2 x 10(-3) M of DTT exhibited the maximal stimulating effect: 3-fold in heart tissue and 4.5-fold in thrombocytes. Only slight 2-fold activation of guanylate cyclase was observed in myocardium in presence of 1 x 10(-4) M nitroprusside, whereas this effect was distinctly augmented up to 26-fold after preincubation of the enzyme with 1 x 10(-4) M of nitroprusside within 45 min at 4 degrees in presence of 2 x 10(-4) M DTT. The stimulating effect of nitroprusside was increased up to 52-fold after addition of 3 micrograms hemoglobin into the sample. Nitroprusside did not show any stimulating effect on the guanylate cyclase activity in rat thrombocytes under experimental conditions used. Possible causes of the phenomenon observed are discussed.
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PMID:[Analogy and differences in properties of soluble forms of guanylate cyclase of the heart and rat blood platelets]. 257 96

Structural analogs of atriopeptins (APs) were compared for their ability to activate particulate guanylate cyclase and bind to specific receptors in rat adrenal membranes. All analogs tested increase Vmax without altering the concentration of substrate required for half-maximum activity or the positive coperativity exhibited by the enzyme. Maximum velocities (pmoles of cGMP produced per min per mg protein) achieved in the absence and presence of APs were 128.3 +/- 6.6 and 283.8 +/- 20.6 using Mn2+-GTP, and 53.7 +/- 3.7 and 149.9 +/- 7.6 using Mg2+-GTP as the substrate, respectively. Although all APs were equally efficacious in activating the enzyme, their rank potency was ANF (8-33) = AP III = AP II greater than AP I when either divalent cation was used as the cofactor. The EC50 for activation of guanylate cyclase by AP I was about 10(-7) M, while that for the other peptides was about 10(-8) M, using either divalent cation cofactor. 125I-labeled ANF bound to rat adrenal membranes with a KD of 5.10(-10) M. Although all APs were equally efficacious in competing with labeled ANF for receptor binding, their rank potency was identical to that for enzyme activation. The Ki for AP I was about 10(-8) M, while that for the other peptides was about 10(-10) M. These data suggest that the carboxy terminal Phe-Arg present in the AP analogs except AP I and critical for biological and receptor-binding activity are also important in coupling receptor-ligand interaction with guanylate cyclase activation. The correlation between the rank order potency for receptor binding, enzyme activation, and the reported physiological actions of APs support the suggestion of a functional coupling between these proteins.
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PMID:Regulation of particulate guanylate cyclase by atriopeptins: relation between peptide structure, receptor binding, and enzyme kinetics. 257 98

1. Escherichia coli heat-stable enterotoxin (ST) induces a secretory diarrhea by binding to receptors on brush borders of intestinal villus cells, activating particulate guanylate cyclase and increasing intracellular concentrations of guanosine 3',5'-cyclic monophosphate (cyclic GMP). 2. However, little is known concerning coupling of receptor-ligand interaction to enzyme activation. 3. This study compares the kinetics of toxin-receptor binding and enzyme activation to better understand this transmembrane signal cascade. 4. Toxin receptor binding was linear and saturable with 50% of maximum displacement of [125I]ST by unlabeled toxin observed at 1.1 x 10(-7) M. ST increased the maximum velocity (Vmax) of guanylate cyclase with magnesium or manganese as the cation substrate without altering the affinity of the enzyme for its substrate or its positive cooperativity. 5. The concentration of toxin yielding half-maximum stimulation of guanylate cyclase was 1.2 x 10(-6) M, 10-fold higher than the affinity of the ligand for its receptor. 6. These data are consistent with the suggestion that ST-receptor interaction is coupled to activation of particulate guanylate cyclase. 7. However, the discrepancy between the affinity of ST for its receptor and its efficacy in activating the enzyme suggests that this coupling is complex. 8. Possible mechanisms underlying this coupling are discussed.
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PMID:Regulation of particulate guanylate cyclase by Escherichia coli heat-stable enterotoxin: receptor binding and enzyme kinetics. 257 46

Soluble guanylate cyclase enzyme was purified from human platelets. The soluble fraction of the lysed platelets was sequentially chromatographed over DEAE-sepharose, GTP-agarose and HPLC size-exclusion columns. About 0.1 mg of purified enzyme could be obtained from 2000 ml of platelet rich plasma. The purified enzyme had the specific activity of 205 nmoles cGMP/mg/min with Mn2+ as cofactor. The enzyme eluted at the 160,000 daltons position from the size-exclusion column. Electrophoresis in the presence of sodium dodecyl sulfate under reducing conditions revealed two subunits of 83,000 and 71,000 daltons respectively.
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PMID:Purification of soluble guanylate cyclase enzyme from human platelets. 257 55

Light causes a rapid, 1.7-fold increase in cyclic GMP concentration in intact squid retinas (Johnson et al. (1986]. To determine whether light-induced changes in cyclic GMP concentration result from activation of guanylate cyclase, we have studied the regulation of guanylate cyclase activity in squid (Loligo pealei) photoreceptors. The enzyme is membrane-associated and activity is enhanced by the detergents Triton X-100 or digitonin. The enzyme requires divalent cations, Mn2+ being preferred over Mg2+. The dependence of enzyme activity on the MnGTP concentration deviates from simple Michaelis-Menten kinetics. Under conditions where a light-induced binding of GTP to the guanine nucleotide regulatory protein can be observed, no light-induced change in guanylate cyclase could be detected.
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PMID:Characterization of guanylate cyclase in squid photoreceptors. 257 64

Substance P enhanced guanylate cyclase (E.C.4.6.1.2) two- to fourfold in pancreas, small intestine, cerebellum, liver, kidney, and lung. Dose response relationship revealed that substance P caused a maximal augmentation of guanylate cyclase activity at concentration of 1 micromolar. Increasing substance P's concentration to the millimolar range caused no further increase in activity. There was an absolute cation requirement for substance P's enhancement of guanylate cyclase activity. Substance P could increase guanylate cyclase activity with either calcium or manganese in the incubation medium but more augmentation was observed with manganese. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of substance P.
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PMID:Cation-dependent substance P activation of the enzyme guanylate cyclase. 258 May 27

Gonadotropin releasing hormone enhanced guanylate cyclase [E.C.4.6.1.2] two- to threefold in pituitary, testis, liver and kidney. Dose response relationships revealed that at a concentration of 1 nanomolar, gonadotropin releasing hormone caused a maximal augmentation of guanylate cyclase activity and that increasing its concentration to the millimolar range caused no further enhancement of this enzyme. There was an absolute cation requirement for gonadotropin releasing hormone's enhancement of guanylate cyclase activity as there was no increase without any cation present. Gonadotropin releasing hormone could increase guanylate cyclase activity with either calcium or manganese in the incubation medium but more augmentation was observed with manganese. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of gonadotropin releasing hormone.
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PMID:Cation-dependent gonadotropin releasing hormone activation of guanylate cyclase. 285 14


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