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)

Members of the receptor-guanylate cyclase (rGC) family possess an intracellular catalytic domain that is regulated by an extracellular receptor domain. GC-C, an intestinally expressed rGC, was initially cloned by homology as an orphan receptor. The search for its ligands has yielded three candidates: STa (a bacterial toxin that causes traveler's diarrhea) and the endogenous peptides uroguanylin and guanylin. Here, by performing Northern and Western blots, and by measuring [125I]STa binding and STa-dependent elevation of cGMP levels, we investigate whether the distribution of GC-C matches that of its endogenous ligands in the rat intestine. We establish that 1) uroguanylin is essentially restricted to small bowel; 2) guanylin is very low in proximal small bowel, increasing to prominent levels in distal small bowel and throughout colon; 3) GC-C messenger RNA and STa-binding sites are uniformly expressed throughout the intestine; and 4) GC-C-mediated cGMP synthesis peaks at the proximal and distal extremes of the intestine (duodenum and colon), but is nearly absent in the middle (ileum). These observations suggest that GC-C's activity may be posttranslationally regulated, demonstrate that the distribution of GC-C is appropriate to mediate the actions of both uroguanylin and guanylin, and help to refine current hypotheses about the physiological role(s) of these peptides.
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PMID:Expression of GC-C, a receptor-guanylate cyclase, and its endogenous ligands uroguanylin and guanylin along the rostrocaudal axis of the intestine. 1096 92

We examined the spatial expression patterns of two orphan receptor guanylyl cyclase genes OlGC4 and OlGC5 during embryogenesis of medaka and characterized the 5' flanking region required for tissue-specific expression of OlGC4 by introducing promoter-GFP fusion constructs into medaka embryos. Expression of OlGC5 is confined to retinal photoreceptor cells, while OlGC4 is expressed in the retina, pineal organ, and olfactory pits. The OlGC4 upstream region between -2374 and +343 is sufficient to drive the sensory organ-specific gene expression. Mutations in the consensus binding sequences for OTX/CRX transcription factors did not impair the reporter gene expression. Our results suggest that the same isoform of guanylyl cyclase is utilized in both photoreceptors and olfactory cells, and that transcription factors other than OTX/CRX primarily activate the OlGC4 expression.
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PMID:Photoreceptors and olfactory cells express the same retinal guanylyl cyclase isoform in medaka: visualization by promoter transgenics. 1104 70

We examined the spatial expression pattern of an orphan receptor guanylyl cyclase gene, OlGC3, during embryogenesis of medaka, and we analyzed the cis-regulatory region required for its photoreceptor cell-specific expression by introducing promoter-green fluorescent protein gene (GFP) fusion constructs into medaka embryos. Zygotic expression of OlGC3 first appears at stage 36 and is confined to retinal photoreceptor cells. The 5' flanking sequence up to -388 is sufficient to drive the photoreceptor cell-specific gene expression. When a mutation was introduced into the orthodenticle-related homeobox (OTX)-binding consensus sequence at -36/-31, reporter gene expression was completely abolished in retinal photoreceptor cells. The mutation seemed not to impair promoter elements for general transcription factors, because ectopic GFP expression in yolk epithelium was not diminished by the same mutation. These results suggest that the proximal cis-regulatory element containing a consensus binding sequence for OTX transcription factors is essential for OlGC3 expression in photoreceptor cells.
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PMID:A cis-regulatory element essential for photoreceptor cell-specific expression of a medaka retinal guanylyl cyclase gene. 1145 26

A novel membrane guanylyl cyclase (membrane GC), OlGC8, was identified in the medaka fish Oryzias latipes by the isolation of full-length cDNA (4958 bp) and genomic DNA (14.3 kbp) clones. Phylogenetic analysis indicated that OlGC8 does not belong in any known vertebrate membrane GC subfamily. OlGC8 consists of an extracellular domain (214 residues), a transmembrane segment (19 residues), and an intracellular protein kinase-like domain (284 residues) and a cyclase catalytic domain (228 residues), although the extracellular domain is about half the length (around 450 residues) of other known vertebrate membrane GCs. OlGC8 transiently expressed in COS-7 cells exhibited only basal guanylyl cyclase activity. None of the known ligands (rat ANP, BNP, CNP, and C-ANF) and various medaka fish tissue extracts, which activated OlGC1, OlGC2, and OlGC7 differentially, stimulated basal activity, suggesting that OlGC8 is an orphan receptor. The OlGC8 gene consists of 24 exons and exists as a single copy on the medaka fish genome. Northern blot hybridization showed that a 5 kb-OlGC8 mRNA was expressed in the kidney and the testis at a high level and a 3.3 kb-OlGC8 mRNA was expressed only in the brain. The RNase protection, RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE), and reverse transcription-polymerase chain reaction (RT-PCR) analyses demonstrated that the 3.3 kb-OlGC8 mRNA detected in the brain is transcribed from the second transcription initiation site, and contains an intron at the position prior to the catalytic domain, the translation product of which appears to be a protein lacking the cyclase catalytic domain.
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PMID:Expression and genomic organization of a medaka fish novel membrane form of guanylyl cyclase/orphan receptor. 1277 30

The mammalian main olfactory epithelium (MOE) recognizes and transduces olfactory cues through a G protein-coupled, cAMP-dependent signaling cascade. Additional chemosensory transduction mechanisms have been suggested but remain controversial. We show that a subset of MOE neurons expressing the orphan receptor guanylyl cyclase GC-D and the cyclic nucleotide-gated channel subunit CNGA3 employ an excitatory cGMP-dependent transduction mechanism for chemodetection. By combining gene targeting of Gucy2d, which encodes GC-D, with patch clamp recording and confocal Ca2+ imaging from single dendritic knobs in situ, we find that GC-D cells recognize the peptide hormones uroguanylin and guanylin as well as natural urine stimuli. These molecules stimulate an excitatory, cGMP-dependent signaling cascade that increases intracellular Ca2+ and action potential firing. Responses are eliminated in both Gucy2d- and Cnga3-null mice, demonstrating the essential role of GC-D and CNGA3 in the transduction of these molecules. The sensitive and selective detection of two important natriuretic peptides by the GC-D neurons suggests the possibility that these cells contribute to the maintenance of salt and water homeostasis or the detection of cues related to hunger, satiety, or thirst.
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PMID:Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium. 1772 38

The Ca(2+)-modulated ONE-GC membrane guanylate cyclase is a central component of the cyclic GMP signaling in odorant transduction. It is a single transmembrane spanning modular protein. Its intracellular region contains Ca(2+) sensor recognition domains linked to GCAP1 and to neurocalcin delta, and a catalytic module. These domains sense increments in free Ca(2+) and stimulate the catalytic module. The present study makes three significant mechanistic advancements. First, to date no ligand for the extracellular (ext) domain is known, for this reason ONE-GC has been deemed as an orphan receptor. The present study identifies its ligand. Uroguanylin stimulates ONE-GC through its ext domain. Second, so far no ligand is known that directly stimulates the catalytic module of any membrane guanylate cyclase. The presented evidence shows that in the presence of the semimicromolar range of free Ca(2+), neurocalcin binds to the catalytic module and stimulates ONE-GC. Thus, ONE-GC has trimodal regulation, two occurring intracellularly and one extracellularly. Third, guanylin, a urine odorant, does not directly stimulate ONE-GC. This challenges the proposed hypothesis that the guanylin odorant signal occurs via ONE-GC [T. Leinders-Zufall, R.E. Cockerham, S. Michalakis, M. Biel, D.L. Garbers, R.R. Reed, F. Zufall, S.D. Munger, Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium, Proc. Natl. Acad. Sci. USA. 104 (2007) 14507-14512].
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PMID:ONE-GC membrane guanylate cyclase, a trimodal odorant signal transducer. 1817 49

Besides soluble guanylyl cyclase (GC), the receptor for NO, there are seven plasma membrane forms of guanylyl cyclase (GC) receptors, enzymes that synthesize the second-messenger cyclic GMP (cGMP). All membrane GCs (GC-A to GC-G) share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic (GC) region. Although the presence of the extracellular domain suggests that all these enzymes function as receptors, specific ligands have been identified for only four of them (GC-A through GC-D). GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart. GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification. GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation. GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Finally, GC-D and GC-G appear to be pseudogenes in the human. In rodents, GC-D is exclusively expressed in the olfactory neuroepithelium, with chemosensory functions. GC-G is the last member of the membrane GC form to be identified. No other mammalian transmembrane GCs are predicted on the basis of gene sequence repositories. In contrast to the other orphan receptor GCs, GC-G has a broad tissue distribution in rodents, including the lung, intestine, kidney, skeletal muscle, and sperm, raising the possibility that there is another yet to be discovered family of cGMP-generating ligands. This chapter reviews the structure and functions of membrane GCs, with special focus on the insights gained to date from genetically modified mice and the role of alterations of these ligand/receptor systems in human diseases.
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PMID:Function and dysfunction of mammalian membrane guanylyl cyclase receptors: lessons from genetic mouse models and implications for human diseases. 1908 25

The contributions of guanylyl cyclases to sensory signaling in the olfactory system have been unclear. Recently, studies of a specialized subpopulation of olfactory sensory neurons (OSNs) located in the main olfactory epithelium have provided important insights into the neuronal function of one receptor guanylyl cyclase, GC-D. Mice expressing reporters such as beta-galactosidase and green fluorescent protein in OSNs that normally express GC-D have allowed investigators to identify these neurons in situ, facilitating anatomical and physiological studies of this sparse neuronal population. The specific perturbation of GC-D function in vivo has helped to resolve the role of this guanylyl cyclase in the transduction of olfactory stimuli. Similar approaches could be useful for the study of the orphan receptor GC-G, which is expressed in another distinct subpopulation of sensory neurons located in the Grueneberg ganglion. In this review, we discuss key findings that have reinvigorated the study of guanylyl cyclase function in the olfactory system.
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PMID:Receptor guanylyl cyclases in mammalian olfactory function. 1994 Oct 39

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