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)

Alpha atrial natriuretic peptide (alpha-ANP) and brain natriuretic peptide are homologous polypeptide hormones involved in the regulation of fluid and electrolyte homeostasis. These two natriuretic peptides apparently share common receptors and stimulate the intracellular production of cyclic GMP as a second messenger. Molecular cloning has defined two types of natriuretic peptide receptors: the ANP-C receptor of relative molecular mass (Mr) 60-70,000 (60-70 K), which is not coupled to cGMP production and may function in the clearance of ANP and the ANP-A receptor of Mr 120-140 K, which is a membrane form of guanylate cyclase in which ligand binding to the extracellular domain activates the cytoplasmic domain of the enzyme. Here we report the cloning and expression of a second human natriuretic peptide-receptor guanylate cyclase, the ANP-B receptor. The ANP-B receptor is preferentially activated by porcine brain natriuretic peptide rather than human alpha-ANP, whereas the ANP-A receptor responds similarly to both natriuretic peptides. These observations may have important implications for our understanding of the central and peripheral control of cardiovascular homeostasis.
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PMID:Differential activation by atrial and brain natriuretic peptides of two different receptor guanylate cyclases. 257 Mar 58

Several studies on the effects of atrial natriuretic polypeptide (ANP) on aldosterone production using isolated adrenal cells have been reported, and they have consistently demonstrated the reduced production of aldosterone by ANP. However, the results on the corticosterone production are sundry. Since ANP selectively activates particulate guanylate cyclase, a possibility could exist that cyclic GMP is the second messenger of ANP signal transduction. In order to demonstrate unequivocally a correlation of cyclic nucleotide levels with the ANP-induced steroidogenesis, we investigated the effects of various concentrations of alpha-human atrial natriuretic polypeptide (alpha-hANP) on aldosterone, corticosterone, cyclic AMP and cyclic GMP production in isolated glomerulosa and fasciculata cells of the rats. Rat glomerulosa and fasciculata cells were obtained by enzymatic digestion of the adrenals of male Wistar rats. The cell pellet was suspended in Hanks balanced salt solution-0.1% BSA buffer and distributed in 900 microliter aliquots to 12 X 75 mm glass tubes. The samples were preincubated for 90 min. in a 37 degrees C water bath under an atmosphere of 5% CO2/95% O2. Aliquots of the test samples were added in a 100 microliter volume and incubated for 4 hr. Total volume of the incubation mixture is 1.0 ml. Aldosterone, cyclic AMP and cyclic GMP were measured by radioimmunoassay and corticosterone was determined by fluorimetric method. The results indicated that alpha-hANP inhibited the secretion of aldosterone and corticosterone in rat glomerulosa cells. Alpha-hANP significantly decreased cyclic AMP production in the rat glomerulosa cells, while it markedly stimulated cyclic GMP production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Stimulated corticosterone production by alpha-human atrial natriuretic polypeptide with increased cyclic GMP production]. 282 46

We studied the effects of organic nitrates and human atrial natriuretic polypeptide (hANP) on relaxation and tissue cyclic guanosine monophosphate (cGMP) levels using isolated canine coronary arteries with and without endothelial injury. Glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), pentaerythritol tetranitrate (PETN), and hANP relaxed both the injured and control coronary arteries, and they increased tissue cGMP levels in a dose-dependent fashion without changing tissue adenosine 3':5'-cyclic phosphate (cAMP) levels. The extent of relaxation was larger and the increase in cGMP was greater in the injured coronary artery than in the control artery. Methylene blue inhibited relaxation induced by GTN and hANP, and decreased tissue cGMP levels in both the injured and control groups. M&B 22,948 enhanced relaxation induced by GTN and hANP and increased tissue cGMP levels in both groups. The results suggest that organic nitrates and hANP relax the coronary artery by directly activating the guanylate cyclase in coronary smooth muscle and that such activation is independent of the endothelium-dependent vasodilator system.
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PMID:Effects of atrial natriuretic polypeptide and organic nitrates on levels of relaxation and cyclic nucleotide of canine coronary artery with and without endothelial injury. 284 5

The atrial natriuretic factor (ANF) R1 receptor from bovine adrenal zona glomerulosa was solubilized with Triton X-100 and purified 13,000-fold, to apparent homogeneity, by sequential affinity chromatography on ANF-agarose and steric exclusion high-performance liquid chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver staining of the purified receptor preparation in the absence or presence of dithiothreitol revealed a single protein band of Mr 130,000. Affinity cross-linking of 125I-ANF to the purified receptor resulted in the labeling of the Mr 130,000 band. The purified receptor bound ANF with a specific activity of 6.8 nmol/mg of protein, corresponding to a stoichiometry of 0.9 mol of ANF bound/mol of Mr 130,000 polypeptide. Starting with 500 g of adrenal zona glomerulosa tissue, we obtained more than 500 pmol of purified receptor with an overall yield of 9%. The purified receptor showed a typical ANF-R1 pharmacological specificity similar to that of the membrane-bound receptor. The homogeneous Mr 130,000 receptor protein displayed high guanylate cyclase activity [1.4 mumol of cyclic GMP formed min-1 (mg of protein)-1] which was not stimulated by ANF. This finding supports the notion that the ANF binding and the guanylate cyclase activities are intrinsic components of the same polypeptide. Finally, the purified ANF-R1 receptor retained its sensitivity to modulation by amiloride, suggesting the presence of an allosteric binding site for amiloride on the receptor protein.
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PMID:Atrial natriuretic factor R1 receptor from bovine adrenal zona glomerulosa: purification, characterization, and modulation by amiloride. 285 53

Incubation of the adrenal membranes at pH 3.5-5.6 resulted in apparent proteolysis of 140 kDa protein to yield a 70 kDa polypeptide containing an ANF-binding site, which could be photoaffinity labeled by [125I]4-azidobenzoyl monoiodo ANF-(4-28). This 70 kDa fragment was found to be disulfide-linked to the remaining segment(s) of the molecule, giving a total apparent Mr of 140,000 when not reduced. The acidic pH-dependent proteolysis was rapid even at 0 degree C, suggesting close association of an endopeptidase with ANF receptor. The proteolysis was inhibited by EDTA, but not by phenylmethanesulfonyl fluoride, N-ethylmaleimide or pepstatin, indicating that the enzyme is a metalloendopeptidase. The inhibition was reversed by ZnCl2 or MnCl2, but not CaCl2 or MgCl2. The adrenal membranes contained guanylate cyclase activity of 1.1 nmol/min/mg protein using Mn-GTP as a substrate, which could be stimulated by 0.1 microM ANF to 2.7 nmol/min/mg. The membranes showed high affinity to ANF-(1-28) and ANF-(4-28), but little affinity to the truncated peptides ANF-(5-25) and ANF-(7-23). After treatment at pH 3.5 and 0 degrees C for 15 min, the membranes retained ANF-binding activity but with broader specificity, exhibiting high affinity to all four peptides above. It was suggested that an acidic metalloendopeptidase in the adrenal membranes may be involved in ANF receptor cleavage.
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PMID:Acidic pH- and metal ion (Zn++ or Mn++)-dependent proteolysis of 140 kDa atrial natriuretic factor receptor in bovine adrenal cortex plasma membranes: evidence for membrane-bound acidic metalloendopeptidase. 289 2

A large number and variety of compounds (acetylcholine, adenosine diphosphate, adenosine triphosphate, arachidonic acid, bradykinin, Ca2+ ionophores, calcitonin gene-related peptide, histamine, hydralazine, substance P, thrombin, and vasoactive intestinal polypeptide) have been shown to relax arterial smooth muscle indirectly. The endothelium in muscular arteries from several species appears to have receptors for these vasodilators. Binding of one of these compounds to its endothelial receptors results in the release (and presumably synthesis) of substance(s) that act on arterial smooth muscle to cause relaxation. The name endothelium-derived relaxing factor (EDRF) has been proposed for the substance or substances responsible for inhibition of contraction. Studies to determine additivity of endothelium-dependent relaxing agents and sensitivity of EDRF-mediated responses to a variety of inhibitors suggest that a single factor or a single common mechanism induces relaxation of vascular smooth muscle. Pharmacological studies have been equivocal with regard to the postulated involvement of phospholipases or arachidonic acid and to the suggestion that EDRF is an oxidative, non-cyclooxygenase product of arachidonate. Experiments on transfer of EDRF and reversal of endothelium-dependent relaxation consistently indicate that EDRF is quite labile. There is convincing evidence that EDRF activates smooth muscle guanylate cyclase, which results in an increase in intracellular cyclic guanosine 3',5'-monophosphate levels. The stimulation of guanylate cyclase by EDRF provides a valuable and sensitive parameter for studies with arteries as well as cells in culture. At present, the identity of EDRF and its role in cardiovascular homeostasis are unknown.
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PMID:Endothelium-derived vascular relaxing factor. 298 29

The vascular endothelium appears obligatory for the expression of the vasodilating property of most polypeptides. A number of polypeptides were studied on the rat aortic ring preparation which was pre-contracted with phenylephrine and only basic polypeptides containing one or more arginine residues elicited relaxation which was endothelium dependent. These peptides included melittin and poly-L-Arg. The basic polypeptide poly-L-Lys also elicited endothelium dependent relaxation, but to a lesser extent than arginine containing polypeptides. Two basic polypeptides, apamin and mastoparan do not promote endothelium dependent relaxation. The former contains arginine between disulfide bonds and in the latter arginine is absent. Basic amino acids and dipeptides which contain arginine, and also polyamines did not elicit relaxation even at high concentrations (10(-3) M). The relaxation elicited by melittin, poly-L-Arg and poly-L-Lys was inhibited by ETYA, NDGA, p-bromophenacyl bromide and not by indomethacin. Methylene blue, an inhibitor of soluble guanylate cyclase, also abolished the relaxation. We suggest that arginine containing peptides may relax vascular smooth muscle by acting directly on the vascular smooth muscle (eg: atriopeptins) and/or or by eliciting release of a relaxing factor(s) from the endothelium.
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PMID:Endothelium dependent vascular relaxation by arginine containing polypeptides. 380 Oct 12

Somatostatin has been shown to inhibit the release of various polypeptide hormones including insulin, glucagon, gastrin, thyroid stimulating hormone, and growth hormone. The mechanism by which somatostatin inhibits the release of these various polypeptide hormones has not been fully elucidated. It has been reported that somatostatin increases the level of the second messenger cyclic GMP in rat brain and in the anterior pituitary gland. The present investigation was designed to determine if these responses seen in the anterior pituitary gland and brain were due to activation of guanylate cyclase [GTP-pyrophosphate lyase (cyclizing), E.C.4.6.1.2.], the enzyme that catalyzes the formation of cyclic GMP. Somatostatin at a concentration of 2 pM enhanced guanylate cyclase activity two-fold in rat cerebrum and anterior pituitary gland. This enhancement of guanylate cyclase activity was also seen in rat liver, pancreas, stomach, and small intestine at the same concentration of somatostatin. Increasing the concentration of somatostatin to 20 microM, caused a marked inhibition of guanylate cyclase activity in all these tissues. Dose-reponse curves done on gastric guanylate cyclase activity revealed that over a concentration range of 2 pM to 0.2 microM, somatostatin had a stimulatory effect on guanylate cyclase activity while at concentrations above 10 microM somatostatin was inhibitory to guanylate cyclase activity. The biphasic pattern of enhancement of guanylate cyclase activity at lower concentrations of somatostatin and inhibition at higher concentrations may help to explain some of the discrepancies seen with previous investigations with somatostatin, hormone release, and cyclic nucleotide metabolism.
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PMID:The interrelationship of somatostatin and guanylate cyclase activity. 611 Jan 70

Because prominent skeletal muscle dysfunction and muscle wasting are seen in both chronic uremia and in primary hyperparathyroidism, and because markedly elevated parathyroid hormone levels occur in both disorders, potential effects of parathyroid hormone on skeletal muscle protein, amino acid, and cyclic nucleotide metabolism were studied in vitro using isolated intact rat epitrochlearis skeletal muscle preparations. Intact bovine parathyroid hormone and the synthetic 1-34 fragment of this hormone stimulated the release of alanine and glutamine from muscle of control but not from chronically uremic animals. This stimulation was dependent upon the concentration of parathyroid hormone added: At 10(5) ng/ml parathyroid hormone increased alanine release 84% and glutamine release 75%. Intracellular levels of alanine and glutamine were not altered by parathyroid hormone. Increasing concentrations of the 1-34 polypeptide decreased [(3)H]leucine incorporation into protein of muscles from both control and uremic animals. Using muscles from animals given a pulse-chase label of [guanido-(14)C]arginine in vivo, parathyroid hormone increased the rate of loss of (14)C label from acid-precipitable protein during incubation and correspondingly increased the rate of appearance of this label in the incubation media. Parathyroid hormone increased muscle cAMP levels by 140% and cGMP levels by 185%, but had no effect on skeletal muscle cyclic nucleotide phosphodiesterase activities as assayed in vitro. Adenylyl cyclase activity in membrane preparations from control but not uremic rats was stimulated by parathyroid hormone in a concentration-dependent fashion. However, no stimulation of guanylyl cyclase activity was noted by parathyroid hormone, although stimulation by sodium azide was present. Incubation of muscles with added parathyroid hormone produced a diminished responsiveness towards epinephrine or serotonin regulation of amino acid release and cAMP formation in the presence compared to the absence of parathyroid hormone. In the absence of parathyroid hormone, detectable inhibition of alanine and glutamine release was produced by 10(-9) M epinephrine, whereas in the presence of parathyroid hormone (1,000 ng/ml) inhibition of alanine and glutamine release required 10(-6) M or greater epinephrine. Resistance to cyclic AMP action as well as inhibition of cyclic AMP formation by parathyroid hormone was found. Preincubation of rat sarcolemma with 1-34 parathyroid hormone produced a decreased activity of the isoproterenol-stimulable adenylyl cyclase activity but there was no apparent change in the concentration of isoproterenol required for one-half maximal and maximal stimulation of the enzyme. These findings suggest that high levels of parathyroid hormone have direct effects on skeletal muscle protein, amino acid, and cyclic nucleotide metabolism in muscle of normal but not uremic animals. Treatment with these high levels of parathyroid hormone in vitro appears to reproduce in normal muscle, the metabolic deficits and loss of hormone responsiveness observed in muscle of chronically uremic animals. It is therefore possible that direct effects of parathyroid hormone on skeletal muscle may account in part for the muscle dysfunction and wasting of primary hyperparathyroidism and chronic uremia.
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PMID:Effects of parathyroid hormone on skeletal muscle protein and amino acid metabolism in the rat. 630 55

Adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) mediate penile erection. We have previously established that adenylate and guanylate cyclase activity is elevated in the diabetic rat penis and aorta. This study investigates the action of papaverine and vasoactive intestinal polypeptide (VIP) on these cyclases. The aortae and penes of Sprague Dawley rats (n = 7) were stimulated with VIP and papaverine. Diabetes mellitus (DM) was induced in Sprague Dawley rats (n = 7) with streptozotocin and the penile and aortic tissues were treated with VIP. The penes, aortae and carotid arteries of New Zealand White rabbits were similarly processed. cAMP and cGMP generation was measured by radioimmunoassay. In all tissues: VIP stimulated cAMP synthesis; VIP did not increase cGMP levels; papaverine was without effect on either cAMP or cGMP synthesis. VIP-stimulated cAMP was significantly enhanced in the diabetic rat penis and aorta; there was also a significant elevation in the basal levels of cGMP in these tissues. These data: (1) consolidate that cAMP is a mediator of penile erection, (2) indicate that papaverine and VIP elicit erection by different mechanisms, (3) suggest that an enhanced penile capacity to generate cAMP in DM may constitute an adaptive response to counteract the previously reported reduction in VIP content and VIP receptors, and (4) indicate that the penile and vascular tissues of the rabbit respond in a similar manner to VIP and papaverine.
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PMID:Effects of papaverine and vasointestinal polypeptide on penile and vascular cAMP and cGMP in control and diabetic animals: an in vitro study. 749 46


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