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 type C natriuretic peptide (CNP)-activated guanylate cyclase (CNP-RGC) is a single-chain transmembrane-spanning protein, predicted to contain both ligand binding and catalytic activities. Upon binding CNP, CNP-RGC catalyzes the formation of cyclic GMP. We now show that the Glu-332 residue residing in the extracellular region of CNP-RGC plays an important role in signal transduction. Deletion of the CNP-RGC intracellular region resulted in the CNP receptor which lacked cyclase activity; deletion or substitution of Glu-332 with His or Lys resulted in almost total loss of both CNP binding and the CNP-dependent cyclase activity without affecting the basal cyclase activity of the mutant proteins. These observations support the general signal transduction model of the subfamily of natriuretic factor receptor cyclases where it is predicted that ligand binding to the extracellular receptor domain of the protein activates the cytosolic catalytic domain, generating the second-messenger cyclic GMP, and identify an amino acid residue of CNP-RGC that plays an important role in CNP signaling.
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PMID:Glutamic acid-332 residue of the type C natriuretic peptide receptor guanylate cyclase is important for signaling. 791 83

The molecular properties of retinal rod guanyl cyclase were investigated. Peptides were derived from a 112-kDa protein previously identified as the particulate bovine retinal rod guanyl cyclase. The peptides showed 100% identity to the deduced amino acid sequence of the cloned human retina-specific membrane guanyl cyclase, whereas identity to the members of the natriuretic peptide receptor guanyl cyclases was 14-59%. The 112-kDa protein was further purified by a new approach using wheat-germ agglutinin chromatography. This indicated N-linked glycosylation in retinal rod guanyl cyclase. N-glycosylation was unexpected from the sequence of the human retina-specific membrane guanyl cyclase, although it is a common property of natriuretic peptide receptors. Therefore, we further analyzed the carbohydrate composition of bovine retinal rod guanyl cyclase by lectin binding using the lectins Galanthus nivalis agglutinin, Sambucus nigra agglutinin, Maackia amurensis agglutinin, Ricinus communis agglutinin, Datura stramonium agglutinin, peanut agglutinin and by chromatography of the purified enzyme using concanavalin-A-Sepharose. The oligosaccharide side chains were of the high-mannose type or hybrid type, probably with mannose, N-acetylglucosamine and sialic acid as terminal sugars. Enzymic deglycosylation by N-glycosidase F was achieved after proteolytic digestion with endoproteinase Glu-C. Lectins neither influenced the basal nor the stimulated guanyl-cyclase activity at low calcium concentrations. Our results indicate that the particulate rod guanyl cyclase represents an unusual new subtype of membrane-bound guanyl cyclases.
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PMID:Bovine retinal rod guanyl cyclase represents a new N-glycosylated subtype of membrane-bound guanyl cyclases. 791 73

We investigated the ultracytochemical localization of particulate guanylate cyclase (GC) in the rat neurohypophysis after activation with rat atrial natriuretic factor (rANF) or porcine brain natriuretic peptide (pBNP). Under our experimental conditions, the presence of GC reaction product indicated that rANF and pBNP were strong activators of particulate GC since samples incubated in basal conditions without rANF or pBNP did not reveal any GC reaction product. The rANF-stimulated GC was localized both to pituicytes and to nerve fibers and endings whereas the pBNP-stimulated GC was present exclusively in nerve fibers and endings. Recently, two subtypes of receptors for natriuretic peptides have been identified as two isoforms of particulate GC [24,50]. Our data indicate that the receptors of the two hormones have a partially distinct distribution in the rat neurohypophysis. In pituicytes, GC reaction product was found on plasma membrane of finger-like processes and on the membranes surrounding the lipid droplets. In nerve fibers and endings, GC reaction product was associated with intracellular membranes. This finding suggests that the enzyme could mediate an internal inhibitory action of these hormones on the release of vasopressin and oxytocin.
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PMID:Detection of particulate guanylate cyclase in rat neurohypophysis after stimulation with ANF and BNP: an ultracytochemical study. 791 1

The role of cyclic 3',5'-guanosine monophosphate (cGMP) as a second messenger in LHRH neurons is not well understood. Recent studies involving nitric oxide, a direct activator of soluble guanylate cyclase (GC), have implicated cGMP in the regulation of LHRH secretion both in vivo and in vitro. Evidence for the membrane-bound form of GC in LHRH neurons has thus far not been reported. In polymerase chain reaction screening of various cell lines for the natriuretic peptide receptors--which represent GCs--we identified both GC-A and GC-B cDNAs by southern blot hybridization in reverse transcribed and amplified extracts of the GT1-7 cell line, an immortalized LHRH neuronal cell line. Subsequent experiments demonstrated that all of the natriuretic peptides elevated cGMP production with a rank order of potency: CNP > ANP > BNP. Time course studies revealed a rapid intracellular accumulation of cGMP following exposure to CNP with a peak at 2.5 min. CNP was some 200-fold more potent than the NO donor, sodium nitroprusside, in stimulating cGMP accumulation in these cells. These data show for the first time the presence of functional mGCs on LHRH cells, and suggest that the natriuretic peptides may also participate in the regulation of LHRH activity.
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PMID:Natriuretic peptides stimulate cyclic GMP production in an immortalized LHRH neuronal cell line. 791 32

Atrial natriuretic factor, originally isolated from the atrium of the heart, has been found to consist of three major groups: atrial natriuretic peptide (ANP), B-form natriuretic peptide (BNP), and C-form natriuretic peptide (CNP). In addition, ANP exists in its precursor form, pro-ANP, an active ANP with a longer peptide chain (urodilatin) and an antiparallel dimer of active ANP. Sites and production of these diverse forms of the peptides are also diverse, depending on pathologic states. Three major subtypes of ANP receptors exist; these include a clearance receptor and two types of a transmembrane receptor with guanylyl cyclase structures in their intracellular domain. The latter exists at least in two forms, one of which is found mainly in the brain. All the actions of ANP mediated by the transmembrane form of ANP receptors are mediated by cGMP generated by the guanylyl cyclase in the cytosolic domain of the receptor. Among the numerous effects of ANP, its major effects are stimulation of natriuresis and diuresis by the kidney through its hemodynamic and tubular effects. In addition, ANP causes vasodilatation and fluid volume reduction by direct actions on vascular smooth muscle cells, and inhibition of secretion of hormones, such as aldosterone, from adrenal cortex and norepinephrine from peripheral adrenergic neurons. Centrally mediated effects on the regulation of the fluid volume may also be important.
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PMID:Atrial natriuretic factor as a volume regulator. 791 52

The natriuretic peptide system is a complicated system comprising at least three endogenous peptides, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide and three receptors, the atrial natriuretic peptide-A receptor (guanylyl cyclase A), the atrial natriuretic peptide-B receptor (guanylyl cyclase B), and the clearance receptor. The accumulated evidence indicates that this system is implicated in the control of blood pressure, body fluid homeostasis, and vascular remodeling as both cardiac hormone and local regulator.
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PMID:The natriuretic peptide family. 792 66

The mechanism underlying the mineralocorticoid escape phenomenon remains unknown. To assess the possible contribution of natriuretic peptides to mineralocorticoid escape, rats were injected with 5 mg deoxycorticosterone acetate for 3 d. Plasma atrial natriuretic factor (ANF) rose to twice basal levels and atrial ANF content decreased significantly by 24 h of treatment. This coincided with renal escape and with a significant increase in urinary cGMP excretion. Plasma ANF remained elevated and atrial ANF content continued to decline by 48 and 72 h while atrial ANF mRNA levels increased significantly only at 72 h. Plasma brain natriuretic peptide did not increase during escape although atrial brain natriuretic peptide mRNA levels increased significantly. Chronically administered HS-142-1 (HS), a specific antagonist of the guanylate cyclase-coupled natriuretic peptide receptors, significantly and dose-dependently impaired the escape phenomenon. The highest dose of HS completely suppressed the increase in urinary cGMP. Despite the continued suppression, partial escape was observed by the end of the observation period. HS alone influenced neither plasma nor tissue or urine parameters. These findings show that despite activation of atrial ANF, blockade of the guanylate cyclase-coupled natriuretic peptide receptors impairs the ability of the kidney to escape the Na+ retaining effect of excess mineralocorticoid in a dose-dependent fashion. Later-acting, unknown mechanisms eventually come into play to mediate the escape phenomenon through a guanylate cyclase-independent pathway. Therefore, ANF of cardiac origin appears to be a major factor initiating mineralocorticoid escape through a guanylate cyclase-dependent pathway.
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PMID:Atrial natriuretic factor significantly contributes to the mineralocorticoid escape phenomenon. Evidence for a guanylate cyclase-mediated pathway. 796 39

Natriuretic peptides act via receptors with intrinsic guanylate cyclase activity to stimulate cGMP production and are thought to be important regulators of neuroendocrine systems. C-Type natriuretic peptide (CNP) is of particular interest in this regard because the highest tissue concentrations of CNP occur in the anterior pituitary, where it is a highly potent stimulator of cGMP production. Here we show that pituitaries of rats and mice contain abundant CNP prohormone messenger RNA (mRNA), but no atrial natriuretic peptide or B-type natriuretic peptide prohormone mRNAs. Using reverse transcriptase-polymerase chain reaction, both A- and B-type natriuretic peptide receptor (GC-A and GC-B, respectively) transcripts were detected in rat and mouse pituitaries, although only the GC-B mRNA was measurable by Northern blotting. Immunohistochemistry revealed CNP-positive cells in the anterior, but not posterior, pituitaries of rats, and the vast majority of these cells were identified as gonadotropes by colocalization of CNP and LH immunoreactivities. Targeted toxicity using GnRH conjugated to the ricin-A chain was used to test whether gonadotropes are also direct targets for GnRH action. The conjugate dose dependently inhibited the proliferation of alpha T3-1 cells (gonadotrope-derived cells with GnRH receptors), but had no such effect on GH3 cells (which do not have GnRH receptors). Culture of rat pituitary cells with the conjugate caused comparable reductions in CNP-stimulated cGMP production, GnRH-stimulated LH release, and CA2+ ionophore (A23187)-stimulated LH release, but did not measurably alter cAMP production in response to pituitary adenylate cyclase-activating polypeptide. We conclude that CNP is synthesized in the pituitary, where it is located predominantly in gonadotropes, and GC-B receptors expressed in the pituitary mediate the direct effects of CNP in gonadotropes. Together with the recent demonstration of CNP synthesis and action in alpha T3-1 cells, the data suggest CNP to be a novel autocrine regulator of gonadotropes.
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PMID:C-type natriuretic peptide (CNP) in the pituitary: is CNP an autocrine regulator of gonadotropes? 798 73

The effects of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) on renal medullary thick ascending limb (mTAL) have not been fully understood. The aim of this study is to examine the second-messenger responses of rat mTAL to ANF, BNP, and CNP. Characterizations of the ANF, BNP, and CNP receptors in mTAL were also performed by radioligand studies. Results showed that ANF and BNP were both capable of eliciting cyclic guanosine monophosphate (cGMP) responses in mTAL. Conversely, no cGMP response was observed upon stimulation by CNP in mTAL. The presence of ANF receptors was demonstrated by radioligand studies. One receptor site was found, and the Kd and maximum binding capacity were 4.0 +/- 0.45 nmol/L and 277.8 +/- 47.7 fmol/mg protein, respectively. BNP receptors were also found in mTAL, and ANF and BNP were sharing the same receptor. On the contrary, no CNP receptor could be shown by radioligand studies. These results suggest that guanylyl cyclase-coupled receptors (atrial natriuretic peptide receptor-A [ANPR-A]) specific for ANF and BNP are present in rat mTAL, while those for CNP (ANPR-B) are absent. ANF and BNP but not CNP act on mTAL to control water excretion.
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PMID:Cyclic guanosine monophosphate responses to atrial natriuretic factor, brain natriuretic peptide, but not C-type natriuretic peptide, and the characterization of their receptors in rat medullary thick ascending limb. 799 Jul 7

We describe a unique transient binding phenomenon for atrial natriuretic peptide (ANP) binding to the natriuretic peptide receptor-A (NPR-A) guanylyl cyclase stably expressed in 293 cells. The time course of ANP binding to intact cells peaked at 15 min followed by a subsequent decrease. Reduced binding was a consequence of an ANP induced low affinity state of NPR-A, and required the receptors' kinase homology domain. In a particulate fraction, ANP-stimulated cGMP production was dependent on ATP as a cofactor, and ATP promoted a lower affinity state. Our findings suggest that the kinase homology domain of NPR-A mediates the regulatory action of ATP, not only for signal transduction, but in the modulation of NPR-A hormone affinity.
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PMID:Hormonal induction of low affinity receptor guanylyl cyclase. 809 19


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