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)

The distribution of binding sites for atrial natriuretic peptide (ANP) has been examined in frozen sections of the guinea pig inner ear by means of autoradiography. The highest density was found in the stria vascularis of all cochlear turns. In membrane preparations of stria vascularis in vitro, the production of the second messenger cGMP was strongly stimulated by synthetic ANP in a dose dependent manner. Adenylate cyclase was neither stimulated nor inhibited by ANP, thus suggesting, that the binding sites coincide with an ANP receptor, which is coupled to guanylate cyclase but not negatively coupled to an adenylate cyclase molecule. The production of cyclic GMP could not be reduced by GDP-beta S, a strong inhibitor of the Gs protein. We conclude the existence of an ANP receptor-guanylate cyclase signal transfer system, similar to the beta 2 receptor-adenylate cyclase system in the inner ear, without coupling to a G protein. ANP might play a role in sodium and water regulation of the endolymph and might antagonize the action of vasopressin.
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PMID:Binding sites of atrial natriuretic peptide (ANP) in the mammalian cochlea and stimulation of cyclic GMP synthesis. 133 79

1. Barrier function and cytosolic free calcium content [Ca2+]i was measured in monolayers of bovine pulmonary artery endothelial cells (BPAEC) and bovine aortic endothelial cells (BAEC). 2. Thrombin (1 u ml-1) increased albumin transfer across monolayers of BPAEC but not BAEC, yet induced biphasic increases in [Ca2+]i in both endothelial cell types, consisting of a rapid, initial phasic component which decayed to a lower, more sustained plateau phase. 3. 4 beta-Phorbol 12-myristate 13-acetate (PMA; 0.3-3000 nM) increased albumin transfer across monolayers of BPAEC and BAEC, but had no effect on basal levels of [Ca2+]i in either endothelial cell type. 4. Treatment of BPAEC and BAEC with forskolin (30 microM), an activator of adenylate cyclase, had no effect on resting transfer of albumin, but inhibited that stimulated by PMA (600 nM). It also inhibited the thrombin (1 u ml-1)-induced increase in albumin transfer across monolayers of BPAEC, but enhanced the plateau phase of the associated increase in [Ca2+]i. 5. Treatment of BPAEC and BAEC with either atriopeptin II (100 nM), an activator of particulate guanylate cyclase, or 8 bromo cyclic GMP (30 microM) had no effect on resting or PMA (600 nM)-stimulated transfer of albumin. Both agents did, however, inhibit the thrombin (1 u ml-1)-induced increase in albumin transfer across monolayers of BPAEC, but had no effect on the associated increase in [Ca2+]i. 6. These data suggest a dissociation between the ability of agents that increase or decrease albumin transfer and their effects on [Ca2+]i. Consequently, activation of protein kinase C may be the major stimulus for trans-endothelial transfer of macromolecular solutes. Endothelial barrier function is enhanced by elevation of either cyclic AMP or cyclic GMP content. Cyclic AMP appears to act by inhibiting the actions of protein kinase C, while cyclic GMP may act to inhibit a key step proximal to activation of this enzyme.
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PMID:Modulation of barrier function of bovine aortic and pulmonary artery endothelial cells: dissociation from cytosolic calcium content. 133 54

The spontaneous contractile force of muscle strips isolated from rabbit urinary bladder dome, base and urethra was dose-dependently inhibited by isoproterenol, an adenylate cyclase activator through beta-adrenoceptors and also by sodium nitroprusside, a guanylate cyclase activator. The relaxation response by isoproterenol was biggest in urinary bladder dome. Percent relaxation to 10(-4) M isoproterenol was 73.6% in bladder dome, 56.1% in bladder base, and 44.1% in urethra. The relaxation response by nitroprusside was biggest in urethra. Percent relaxation to 10(-4) M sodium nitroprusside was 34.8% in bladder dome, 51.2% in bladder base, and 63.2% in urethra. Cyclic adenosine monophosphate (cAMP) accumulation by isoproterenol was greatest in dome. cAMP levels increased by 150% in bladder dome, by 74% in bladder base and by 80% in urethra after 1 min over basal levels to become stable for 5 min. Cyclic guanosine monophosphate (cGMP) accumulation by sodium nitroprusside was greatest in urethra. cGMP levels increased by 445% in urethra after 1 min over basal levels and by 320% in dome, by 380% in base and by 1,100% in urethra after 5 min over basal levels. Dibutyryl cAMP relaxed the dome, base and urethra. 8-bromo cGMP also relaxed them. These results suggest that the role of cGMP is mainly related to urethral relaxation, whereas the role of cAMP is mainly related to urinary bladder relaxation.
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PMID:Regional difference in functional roles of cAMP and cGMP in lower urinary tract smooth muscle contractility. 133 26

We reported previously that atrial natriuretic factor (ANF) and the ANF clearance receptor binding peptide, C-ANF(4-23)-NH2 (C-ANF), inhibit catecholamine (CA) release from rat, nerve growth factor-treated pheochromocytoma cells (PC12 cells) by a guanylate cyclase independent mechanism. This mechanism is most likely a pertussis toxin (PTX)-sensitive inhibition of adenylate cyclase. This study examines the role of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), in mediating atrial natriuretic factor effects on depolarization-induced CA release from PC12 cells. The following evidence supports the hypothesis that the neuromodulatory action of atrial peptides is independent of increases in cGMP: 1) ANF does not potentiate the inhibitory effect of C-ANF on CA release or cAMP generation but still elevates cGMP concentrations in the presence of C-ANF; 2) the neuromodulatory effects of ANF and C-ANF are blocked or reversed by a membrane permeable analog of cAMP, dibutyryl cAMP; 3) ANF and C-ANF attenuate CA release in the presence of a maximally effective concentration of dibutyryl cGMP; 4) the inhibitory effect of dibutyryl cGMP is PTX-insensitive whereas the atrial peptide effect is blocked by PTX-pretreatment; and 5) dibutyryl cGMP is without effect on adenylate cyclase. These data are consistent with the hypothesis that ANF and C-ANF act via the ANF clearance (R2) receptor to suppress adenylate cyclase activity and neurotransmission.
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PMID:Neuromodulatory effects of atrial natriuretic peptides correlate with an inhibition of adenylate cyclase but not an activation of guanylate cyclase. 134 40

Adenylate and guanylate cyclases, having different but related substrates, are a paradigm for the study of substrate discrimination. A prokaryotic adenylate cyclase gene, phylogenetically related to eukaryotic counterparts, was screened for mutants remodelling the enzyme's specificity. In a first step, a mutant was selected displaying a significant level of guanylate cyclase activity. This was due to a point mutation destroying most of the adenylate cyclase activity. A second selection step restored most of the original activity. This resulted from an additional mutation in the same region, thus permitting the first identification of a functional domain in adenylate and guanylate cyclases.
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PMID:From adenylate cyclase to guanylate cyclase. Mutational analysis of a change in substrate specificity. 135 50

The 98 amino acid (a.a.) N-terminus of the 126 a.a. atrial natriuretic factor (ANF) prohormone contains three peptides consisting of a.a. 1-30 (proANF 1-30), a.a. 31-67 (proANF 31-67) and a.a. 79-98 (proANF 79-98) with blood pressure lowering, sodium and/or potassium excreting properties similar to atrial natriuretic factor (a.a. 99-126, C-terminus of prohormone). ProANF 1-30 and proANF 31-67 have separate and distinct receptors from ANF in both vasculature and in the kidney to help mediate the above effects. At the cellular level proANFs 1-30, 31-67, and 79-98 as well as ANF's effects are mediated by enhancement of the guanylate cyclase (EC 4.6.1.2)-cyclic GMP system in vasculature and in the kidney. These peptides from the N-terminus of the ANF prohormone circulate normally in man and in all animal species tested. The object of the present investigation was to determine if these peptides have the ability to enhance either guanylate cyclase and/or adenylate cyclase in a variety of other tissues in addition to kidney and vasculature. ProANF 1-30, proANF 31-67, proANF 79-98, and ANF all increased rat lung, liver, heart and testes, but not spleen, particulate guanylate cyclase 2- to 3-fold at their 100 nM concentrations. Dose response curves revealed that maximal stimulation of particulate guanylate cyclase activity by these newly discovered peptides was at their 1 microM concentrations, with no further increase in activity above their 1 microM concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Peptides from the N-terminus of the atrial natriuretic factor prohormone enhance guanylate cyclase activity and increase cyclic GMP levels in a wide variety of tissues. 135 37

Electrical field stimulation (EFS) of nerves intrinsic to the opossum lower esophageal sphincter (LES) produces LES relaxation, an increase in its guanosine 3',5'-cyclic monophosphate (cGMP) content, and hyperpolarization of its circular muscle membrane potential difference. Activation of esophageal nerves produces an analogous hyperpolarization of the circular esophageal smooth muscle. These studies test the hypothesis that cGMP is an intracellular mediator of this hyperpolarization. The transmembrane potential difference of circular smooth muscle cells was recorded with glass microelectrodes. Nerve-mediated smooth muscle hyperpolarization was evoked by EFS (1 ms, 50 V pulses). Forskolin, an activator of adenylate cyclase, and sodium nitroprusside, an activator of guanylate cyclase, produced hyperpolarization. Cystamine and methylene blue, inhibitors of guanylate cyclase, blocked the hyperpolarization elicited by sodium nitroprusside, but not that by forskolin. Both also reversibly abolished the hyperpolarization evoked by EFS. Membrane-permeable derivatives of cGMP produced a concentration-dependent hyperpolarization. These data support the hypothesis that cGMP is an intracellular mediator of nerve-induced esophageal smooth muscle hyperpolarization.
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PMID:Guanylate cyclase inhibitors: effect on inhibitory junction potentials in esophageal smooth muscle. 135 3

Atrial natriuretic peptide (ANP) inhibits aldosterone secretion evoked by its physiological secretagogues by a mechanism(s) likely to involve intracellular messengers. When one examines the results of various investigations so far, this premise, although not definitive yet, seems to be supported. Therefore a brief perspective on the cellular messengers of the various secretagogues is provided before the inquiry into the possible mechanism of action of ANP. The receptors of ANP in the adrenal cells have been identified and characterized. ANP inhibits adenylate cyclase in various tissues through an inhibitory G protein, which appears to explain in part the inhibitory effect of ANP on adrenocorticotropin-induced aldosterone secretion. However, there could be other possible effects of ANP as discussed. ANP probably inhibits aldosterone secretion evoked by angiotensin II and potassium by interfering with the appropriate changes in calcium flux and cell calcium concentration, concomitants of stimulation by these secretagogues. The potential modes of these effects are probed. The role of guanosine 3',5'-cyclic monophosphate, which is increased by receptor activation of guanylate cyclase by ANP and is thought to play a major role in the biological effects of ANP in some other tissues, remains controversial in the aldosterone-lowering effect of ANP, and this is also discussed extensively in this review.
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PMID:Atrial natriuretic peptide-induced inhibition of aldosterone secretion: a quest for mediator(s) 135 32

We recently demonstrated the synthesis and secretion of an atriopeptin (AP)-like prohormone in rat neonatal and adult cortical kidney cell cultures. However, these cultures contained proximal as well as distal tubular epithelial cells; thus characterization of the peptide synthetic cell was not possible. Also, by immunohistochemical techniques, we localized this AP-like prohormone to the distal cortical nephron in adult rat kidney. In this study, we examined further details of the kidney cortical cell type that expresses and secretes this AP-like peptide in adult renal cortical cell cultures, its regulation by adenylate cyclase via adenosine 3',5'-cyclic monophosphate (cAMP) generation, and its ability to stimulate guanylate cyclase. Tubular fragments were derived from cortical tissue of adult Sprague-Dawley rats and separated into four fractions on Percoll density gradient. Cell cultures generated from fraction 3 secreted 5- to 10-fold the amount of this renal peptide compared with fractions 2 and 4. Further cell culture characterization was performed by agonist-stimulated cAMP formation, kallikrein localization, and prostaglandin E2 formation. From these analyses, it was determined that tissue band 3 was enriched for distal cortical connecting tubules. To further evaluate whether mammalian distal nephron synthesizes an AP-like protein, we determined that two immortalized mouse cell lines, derived from either the distal convoluted tubule or cortical collecting tubule, synthesized a radiolabeled AP after being pulsed with [35S]-methionine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization, synthetic regulation, and biology of renal atriopeptin-like prohormone. 135 79

1. The signal transduction pathway for vasorelaxation induced by human alpha-calcitonin gene-related peptide (human alpha-CGRP) was studied in rat thoracic aortic rings preconstricted with noradrenaline (10(-7) M). 2. Vasorelaxation by human alpha-CGRP was inhibited by haemoglobin (10(-6) M) and methylene blue (10(-5) M) but was unaffected by ibuprofen (10(-5) M). 3. Acetylcholine caused a 16 fold increase in levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP) with levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) being unaltered. Human alpha-CGRP caused a 12 fold increase in levels of cyclic GMP but, in contrast to acetylcholine, evoked a 2.5 fold rise in levels of cyclic AMP. The rises in cyclic nucleotides evoked by human alpha-CGRP and acetylcholine were dependent on the presence of an intact endothelium. 4. NG-nitro-L-arginine (L-NOARG: 10(-5) M), which inhibits nitric oxide synthetase, inhibited the relaxant response to human alpha-CGRP and cyclic GMP accumulation without affecting the cyclic AMP accumulation. 5. The data presented in this paper suggests that human alpha-CGRP relaxes the rat thoracic aorta by releasing nitric oxide and stimulating guanylate cyclase. The stimulation of adenylate cyclase by human alpha-CGRP probably precedes the activation of nitric oxide synthase but could be unrelated to the relaxant response.
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PMID:Human alpha-calcitonin gene-related peptide stimulates adenylate cyclase and guanylate cyclase and relaxes rat thoracic aorta by releasing nitric oxide. 136 70


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