Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Dictyostelium discoideum extracellular cAMP stimulates guanylyl cyclase and phospholipase C; the latter enzyme produces Ins(1,4,5)P3 which releases Ca2+ from internal stores. The following data indicate that intracellular Ca2+ ions inhibit guanylyl cyclase activity. 1) In vitro, Ca2+ inhibits guanylyl cyclase with IC50 = 41 nM Ca2+ and Hill-coefficient of 2.1. 2) Extracellular Ca2+ does not affect basal cGMP levels of intact cells. In electro-permeabilized cells, however, cGMP levels are reduced by 85% within 45 s after addition of 10(-6) M Ca2+ to the medium; halfmaximal reduction occurs at 200 nM extracellular Ca2+. 3) Receptor-stimulated activation of guanylyl cyclase in electro-permeabilized cells is also inhibited by extracellular Ca2+ with half-maximal effect at 200 nM Ca2+. 4) In several mutants an inverse correlation exists between receptor-stimulated Ins(1,4,5)P3 production and cGMP formation. We conclude that receptor-stimulated cytosolic Ca2+ elevation is a negative regulator of receptor-stimulated guanylyl cyclase.
 ...
PMID:Inhibition of receptor-stimulated guanylyl cyclase by intracellular calcium ions in Dictyostelium cells. 135 66

Atrial natriuretic peptide (ANP) binds to the guanylyl cyclase-A (GC-A) receptor found in tissues such as the kidney and adrenal gland, resulting in marked elevations of the intracellular signaling molecule, cGMP. Here, GC-A is shown to exist as a phosphoprotein when expressed in human embryonic 293 cells. The 32P is principally associated with phosphoserine, with only trace amounts of phosphothreonine. The addition of ANP causes a time-dependent dephosphorylation of the receptor, as well as desensitization, which is not due to an ANP-mediated decrease in the amount of receptor protein. The mobility of GC-A on sodium dodecyl sulfate-polyacrylamide gel electrophoresis increases after treatment of cells with ANP, and protein phosphatase 2A induces the same mobility shift. The protein phosphatase also catalyzes dephosphorylation of GC-A, and this is directly correlated with decreases in ANP-stimulatable guanylyl cyclase activity. Okadaic acid, an inhibitor of protein phosphatase 2A, blocks both the dephosphorylation and the desensitization. Therefore, in contrast to many other cell surface receptors, GC-A is desensitized by ligand-induced dephosphorylation.
 ...
PMID:Dephosphorylation of the guanylyl cyclase-A receptor causes desensitization. 135 76

Several low molecular weight compounds are capable of activating soluble guanylyl cyclase. Recent evidence suggests that some of these are formed under physiological conditions: the nitric oxide radical, carbon monoxide and the hydroxyl radical. Thus, multiple signal transduction pathways appear to exist that form a family of guanylyl cyclase activating factors and thereby regulate the intracellular cyclic guanosine 3',5'-monophosphate level.
 ...
PMID:NO., CO and .OH. Endogenous soluble guanylyl cyclase-activating factors. 135 61

Three different guanylyl cyclase cell receptors are known, but others will likely be discovered within the next few years. The general function of these receptors appear to relate to the regulation of fluid volume or fluid movement. New receptors, or possibly the currently known receptors, therefore, may be discovered in areas of the body where fluid volume regulation is important. Such fluids whose volume or composition might be regulated by guanylyl cyclase receptors include synovial fluid, uterine/oviductal luminal fluid, follicular fluid, aqueous humor, cerebral spinal fluid, seminiferous tubule luminal fluid, epididymal luminal fluid, seminal plasma, and airway luminal fluid. The function of the heterodimeric forms of guanylyl cyclase appear to relate to a primary regulation of nitric oxide (or similar molecules) concentrations, which are in turn regulated by a Ca2+/calmodulin-sensitive nitric oxide synthase.
 ...
PMID:Receptor guanylyl cyclases. 135 64

Previous studies have demonstrated that the Dictyostelium G alpha subunit G alpha 2 is essential for the cAMP-activation of adenylyl cyclase and guanylyl cyclase and that g alpha 2 null mutants do not aggregate. In this manuscript, we extend the analysis of the function of G alpha 2 in regulating downstream effectors by examining the in vivo developmental and physiological phenotypes of both wild-type and g alpha 2 null cells carrying a series of mutant G alpha 2 subunits expressed from the cloned G alpha 2 promoter. Our results show that wild-type cells expressing G alpha 2 subunits carrying mutations G40V and Q208L in the highly conserved GAGESG (residues 38-43) and GGQRS (residues 206-210) domains, which are expected to reduce the intrinsic GTPase activity, are blocked in multicellular development. Analysis of down-stream effector pathways essential for mediating aggregation indicates that cAMP-mediated activation of guanylyl cyclase and phosphatidylinositol-phospholipase C (PI-PLC) is almost completely inhibited and that there is a substantial reduction of cAMP-mediated activation of adenylyl cyclase. Moreover, neither mutant G alpha 2 subunit can complement g alpha 2 null mutants. Expression of G alpha 2(G43V) and G alpha 2(G207V) have little or no effect on the effector pathways and can partially complement g alpha 2 null cells. Our results suggest a model in which the dominant negative phenotypes resulting from the expression of G alpha 2(G40V) and G alpha 2(Q208L) are due to a constitutive adaptation of the effectors through a G alpha 2-mediated pathway. Analysis of PI-PLC in g alpha 2 null mutants and in cell lines expressing mutant G alpha 2 proteins also strongly suggests that G alpha 2 is the G alpha subunit that directly activates PI-PLC during aggregation. Moreover, overexpression of wild-type G alpha 2 results in the ability to precociously activate guanylyl cyclase by cAMP in vegetative cells, suggesting that G alpha 2 may be rate limiting in the developmental regulation of guanylyl cyclase activation. In agreement with previous results, the activation of adenylyl cyclase, while requiring G alpha 2 function in vivo, does not appear to be directly carried out by the G alpha 2 subunit. Our data are consistent with adenylyl cyclase being directly activated by either another G alpha subunit or by beta gamma subunits released on activation of the G protein containing G alpha 2.
 ...
PMID:Amino acid substitutions in the Dictyostelium G alpha subunit G alpha 2 produce dominant negative phenotypes and inhibit the activation of adenylyl cyclase, guanylyl cyclase, and phospholipase C. 135 76

HS-142-1, a novel microbial product, blocked 125I-labeled rat atrial natriuretic peptide (rANP) (= ANF(99-126)) binding to bovine adrenocortical membranes, where guanylyl cyclase-containing receptors are predominantly expressed. However, HS-142-1 only slightly inhibited [125I]rANP binding to bovine lung membranes where only a small portion of binding sites are coupled to guanylyl cyclase. Further, HS-142-1 only recognized the 135 kDa ANP receptor, which is considered to be the guanylyl cyclase-containing receptor based on the results obtained in affinity cross-linking studies with bovine adrenocortical and lung membranes. Under identical conditions, Atriopeptin I selectively recognized guanylyl cyclase-free receptors both in binding and affinity cross-linking experiments. When injected intravenously (1 mg/kg) to anesthetized rats, HS-142-1 abolished ANP-induced diuresis and natriuresis. These results suggest that HS-142-1 works in vivo through a specific interaction with the ANP functional receptor, and that HS-142-1 will be a powerful tool for understanding the physiological roles of ANP in distinction from its pharmacological effects.
 ...
PMID:HS-142-1, a novel nonpeptide atrial natriuretic peptide (ANP) antagonist, blocks ANP-induced renal responses through a specific interaction with guanylyl cyclase-linked receptors. 135 44

Cyclic nucleotides are major intracellular mediators in the signal transduction events in synaptic neurotransmission of the CNS. Intracellular Ca2+ is known to regulate adenylyl cyclase (AC) in a calmodulin (CaM)-dependent manner, and guanylyl cyclase (GC), in an indirect manner through CaM-sensitive nitric oxide synthase. To ascertain the physiological significance of cyclic nucleotide second messenger systems, we have localized the mRNAs encoding AC, GC, and CaM in the rat brain by in situ hybridization using 35S-labeled RNA probes. The AC mRNA is widely distributed throughout the brain; strong hybridization signal was observed in the granular layers of the cerebellum, in the pyramidal and granule cells of the hippocampus, and in the olfactory system. These AC mRNA localizations are compatible with the distribution of Ca2+/CaM-sensitive AC activities. In contrast to AC mRNA distribution, GC mRNA has a more limited distribution. Significant signals were observed in the striatum, in the pyramidal and granule cells of the hippocampus, in the olfactory system, in the inferior and superior colliculus, in the Purkinje cells of the cerebellum, in the locus coeruleus, and in many pyramidal cells in the layers II-III and V of the cerebral cortex, and mainly, in the occipital cortex. In some discrete brain regions, a close correlation was found between enzyme activity and mRNA hybridization signal of GC. The distinct distribution of AC and GC mRNAs suggests that different cyclic nucleotide second messenger systems have specialized functions. On the other hand, CaM mRNA was colocalized with the AC and GC mRNA, but its distribution was more abundant and specific for neuronal cells, since there was little hybridization signal with CaM probe in neuronal fiber regions such as the corpus callosum and the anterior commissure. The high expression of CaM mRNA in neuronal cells is in agreement with its biochemical role in the regulation of various enzymes. Results of the present study should help in analyzing the role of cyclic nucleotides and CaM in physiological and pathological situations in the CNS.
 ...
PMID:Localization of adenylyl and guanylyl cyclase in rat brain by in situ hybridization: comparison with calmodulin mRNA distribution. 135 44

We have isolated and characterized cDNA clones encoding the human retinal guanylyl cyclase (retGC), a novel member of the membrane guanylyl cyclase gene family. Like other membrane guanylyl cyclases, the 1101 aa retGC is predicted to have a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, such as natriuretic peptide receptors, retGC has a relatively high basal level of activity when expressed in human 293 cells. cGMP production by retGC is unaffected by any of the known natriuretic peptides. In situ hybridization analysis of a variety of rhesus monkey tissues showed retGC transcripts to be localized exclusively along the retinal outer nuclear layer, corresponding to the nuclei of the rod and cone photoreceptor cells. Our results suggest that retGC may synthesize cGMP required for recovery of the dark state after phototransduction.
 ...
PMID:Molecular cloning of a retina-specific membrane guanylyl cyclase. 135 71

Most of the physiological actions of atrial natriuretic peptide (ANP) may be attributed to activation of the natriuretic peptide receptor-A (NPR-A) guanylyl cyclase. We report here that truncation of the NPR-A cytoplasmic domain results in increased expression of cell surface ANP binding sites. The truncated receptor exhibited a hyperbolic time course for ANP binding and had a high affinity for [125I]hANP, Kd = 8 pM. Cells expressing truncated NPR-A were used as an immunogen to obtain monoclonal antibodies against the native conformation of the extracellular domain. These antibodies were used to select for high levels of stable NPR-A expression in 293 cells, by fluorescence-activated cell sorting. Disuccinimidyl suberate cross-linked [125I]ANP to 135-kDa NPR-A on intact cells. Monoclonal antibody immunoprecipitation of 35S-labeled proteins revealed NPR-A size heterogeneity, with 135- and 125-kDa species. A synthetic peptide antibody directed against the extracellular domain immunoprecipitated 125-kDa NPR-A, but recognized both sizes of receptor by Western blotting. The 125-kDa NPR-A did not bind to or cross-link ANP. NPR-A size variants were expressed on the cell surface, and heterogeneity was removed by deglycosylation with protein:N-glycosidase F. Our results suggest that the degree of N-linked glycosylation of the NPR-A extracellular domain influences the ability to bind ANP.
 ...
PMID:Human natriuretic peptide receptor-A guanylyl cyclase. Hormone cross-linking and antibody reactivity distinguish receptor glycoforms. 135 91

HS-142-1, a novel polysaccharide, of microbial origin had been characterized as a specific antagonist of guanylyl cyclase-linked atrial natriuretic peptide (ANP) receptors (ANP-GC receptor) in bovine adrenal cortex. The effect of HS-142-1 on ANP receptors of rat glomeruli were examined. HS-142-1 blocked rat ANP (r-ANP)-stimulated cGMP production in a concentration-dependent manner, although it caused only slight inhibition in the specific binding of [125I]-rANP to the glomeruli where only a small portion of the binding sites are coupled to guanylyl cyclase. HS-142-1 recognized the 135K ANP receptor which is thought to be ANP-GC receptors but did not recognized 60K receptor, guanylyl cyclase-free type from affinity cross-linking studies with glomerular membranes. These results indicate that HS-142-1 is a specific antagonist for the ANP-GC receptor in rat glomeruli, and that it will be a powerful tool for understanding the physiological roles of ANP in renal responses.
 ...
PMID:HS-142-1, a novel polysaccharide of microbial origin, specifically recognizes guanylyl cyclase-linked ANP receptor in rat glomeruli. 135 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>