guanylyl cyclase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2018/04/08 00:36:41」(JST)

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Guanylate cyclase
catalytic domain of human soluble guanylate cyclase 1. PDB 3uvj
Identifiers
EC number	4.6.1.2
CAS number	9054-75-5
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

Guanylate cyclase (EC 4.6.1.2, also known as guanyl cyclase, guanylyl cyclase, or GC) is a lyase enzyme. Guanylate cyclase is often part of the G protein signaling cascade that is activated by low intracellular calcium levels and inhibited by high intracellular calcium levels. In response to calcium levels, guanylate cyclase synthesizes cGMP from GTP. cGMP keeps cGMP-gated channels open, allowing for the entry of calcium into the cell. Like cAMP, cGMP is an important second messenger that internalizes the message carried by intercellular messengers such as peptide hormones and NO, and can also function as an autocrine signal. Depending on cell type, it can drive adaptive/developmental changes requiring protein synthesis. In smooth muscle, cGMP is the signal for relaxation, and is coupled to many homeostatic mechanisms including regulation of vasodilaton, vocal tone, insulin secretion, and peristalsis. Once formed, cGMP can be degraded by phosphodiesterases, which themselves are under different forms of regulation, depending on the tissue.

Reaction

Guanylate cyclase catalyzes the reaction of guanosine triphosphate (GTP) to 3',5'-cyclic guanosine monophosphate (cGMP) and pyrophosphate:

• GTP

• cGMP

Effects

Guanylate cyclase is found in the retina (RETGC) and modulates phototransduction in rods and cones. It is part of the calcium negative feedback system that is activated in response to the hyperpolarization of the photoreceptors by light. This causes less intracellular calcium, which stimulates guanylate cyclase-activating proteins (GCAPs). Studies have shown that cGMP synthesis in cones is about 5-10 times higher than it is in rods, which may play an important role in modulating cone adaption to light. In addition, studies have shown that zebrafish express a higher number of GCAPs than mammals, and that zebrafish GCAPs can bind at least three calcium ions.

Guanylate cyclase 2C (GC-C) is an enzyme expressed mainly in intestinal neurons. Activation of GC-C amplifies the excitatory cell response that is modulated by glutamate and acetylcholine receptors. GC-C, while known mainly for its secretory regulation in the intestinal epithelium, is also expressed in the brain. To be specific, it is found in the somata and dendrites of dopaminergic neurons in the ventral tegmental area (VTA) and the substantia nigra. Some studies implicate this pathway as having a role in attention deficiency and hyperactive behavior.

Soluble guanylate cyclase contains a molecule of heme, and is activated primarily by the binding of nitric oxide (NO) to that heme. sGC is primary receptor for nitric oxide (NO) a gaseous, membrane-soluble neurotransmitter. sGC expression has been shown to be highest in the striatum compared to other brain regions and has been explored as a possible candidate for restoring striatal dysfunction in Parkinson's disease. sGC acts as an intracellular intermediary for regulating dopamine and glutamate. Upregulation, which creates neuronal sensitivity, of the cGMP in a dopamine-depleted striatum has been associated with the symptoms of Parkinson's. Increased intracellular cGMP has been shown to contribute to excessive neuron excitability and locomotor activity. Activation of this pathway can also stimulate presynaptic glutamate release and cause an upregulation of AMPA receptors postsynaptically.

Types

There are membrane-bound (type 1, guanylate cyclase-coupled receptor) and soluble (type 2, soluble guanylate cyclase) forms of guanylate cyclases.

Membrane bound guanylate cyclases include an external ligand-binding domain (e.g., for peptide hormones such as BNP and ANP), a transmembrane domain, and an internal catalytic domain homologous to adenylyl cyclases. Recently, a directly light-gated guanylate cyclase has been discovered in an aquatic fungus.

In the mammalian retina, two forms of guanylate cyclase have been identified, each encoded by separate genes; RETGC-1 and RETGC-2. RETGC-1 has been found to be expressed in higher levels in cones compared to rod cells. Studies have also shown that mutations in the RETGC-1 gene can lead to cone-rod dystrophy by disrupting the phototransduction processes.

Mutations

Cone dystrophy (COD) is a retinal degradation of photoreceptor function wherein cone function is lost at the onset of the dystrophy but rod function is preserved until almost the end. COD has been linked to several genetic mutations including mutations in the guanylate cyclase activator 1A (GUCA1A) and guanylate cyclase 2D (GUY2D) among other enzymes. To be specific, GUY2D codes for RETGC-1, which is involved in cone adaptation and photoreceptor sensitivity by synthesizing cGMP. Low concentrations of calcium cause the dimerization of RETGC-1 proteins through stimulation from guanylate cyclase-activating proteins (GCAP). This process happens at amino acids 817-857, and mutations in this region increase RETGC-1 affinity for GCAP. This works to alter the calcium sensitivity of the neuron by allowing mutant RETGC-1 to be activated by GCAP at higher calcium levels than the wild-type. Because RETGC-1 produces cGMP, which keeps cyclic nucleotide-gated channels open allowing the influx of calcium, this mutation causes extremely high intracellular calcium levels. Calcium, which plays many roles in the cell and is tightly regulated, disrupts the membrane when it appears in excess. Also, calcium is linked to apoptosis by causing the release of cytochrome c. Therefore, mutations in the RETGC-1 can cause COD by increasing intracellular calcium levels and stimulating cone photoreceptor death.

See also

• Adenylyl cyclase
• Cyclic guanosine monophosphate
• Guanylyl cyclase activator (protein)

External links

• Guanylate Cyclase at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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English Journal

• Nitric Oxide Regulation of Na, K-ATPase Activity in Ocular Ciliary Epithelium Involves Src Family Kinase.

• Shahidullah M, Mandal A, Wei G, Delamere NA.Author information Department of Physiology, University of Arizona, Tucson, Arizona.AbstractThe nitric oxide (NO) donor sodium nitroprusside (SNP) is known to reduce aqueous humor (AH) secretion in the isolated porcine eye. Previously, SNP was found to inhibit Na,K-ATPase activity in nonpigmented ciliary epithelium (NPE), AH-secreting cells, through a cGMP/protein kinase G (PKG)-mediated pathway. Here we show Src family kinase (SFK) activation in the Na,K-ATPase activity response to SNP. Ouabain-sensitive (86) Rb uptake was reduced by >35% in cultured NPE cells exposed to SNP (100 µM) or exogenously added cGMP (8-Br-cGMP) (100 µM) and the SFK inhibitor PP2 (10 µM) prevented the response. Ouabain-sensitive ATP hydrolysis was reduced by ∼40% in samples detected in material obtained from SNP- and 8-Br-cGMP-treated cells following homogenization, pointing to an intrinsic change of Na,K-ATPase activity. Tyrosine-10 phosphorylation of Na,K-ATPase α1 subunit was detected in SNP and L-arginine-treated cells and the response prevented by PP2. SNP elicited an increase in cell cGMP. Cells exposed to 8-Br-cGMP displayed SFK activation (phosphorylation) and inhibition of both ouabain-sensitive (86) Rb uptake and Na,K-ATPase activity that was prevented by PP2. SFK activation, which also occurred in SNP-treated cells, was suppressed by inhibitors of soluble guanylate cyclase (ODQ; 10 µM) and PKG (KT5823; 1 µM). SNP and 8-Br-cGMP also increased phosphorylation of ERK1/2 and p38 MAPK and the response prevented by PP2. However, U0126 did not prevent SNP or 8-Br-cGMP-induced inhibition of Na,K-ATPase activity. Taken together, the results suggest that NO activates guanylate cyclase to cause a rise in cGMP and subsequent PKG-dependent SFK activation. Inhibition of Na,K-ATPase activity depends on SFK activation. J. Cell. Physiol. 229: 343-352, 2014. © 2013 Wiley Periodicals, Inc.
• Journal of cellular physiology.J Cell Physiol.2014 Mar;229(3):343-52. doi: 10.1002/jcp.24454.
• The nitric oxide (NO) donor sodium nitroprusside (SNP) is known to reduce aqueous humor (AH) secretion in the isolated porcine eye. Previously, SNP was found to inhibit Na,K-ATPase activity in nonpigmented ciliary epithelium (NPE), AH-secreting cells, through a cGMP/protein kinase G (PKG)-mediated p
• PMID 24037816

• Tempol-nebivolol therapy potentiates hypotensive effect increasing NO bioavailability and signaling pathway.

• Bertera FM, Santa-Cruz DM, Balestrasse KB, Gorzalczany SB, Höcht C, Taira CA, Polizio AH.Author information Department of Pharmacology, University of Buenos Aires , Buenos Aires , Argentina.AbstractAbstract Nebivolol is a third generation beta blocker with endothelial nitric oxide synthase (eNOS) agonist properties. Considering the role of reactive oxygen species (ROS) in the uncoupling of eNOS, we hypothesized that the preadministration of an antioxidant as tempol, could improve the hypotensive response of nebivolol in normotensive animals increasing the nitric oxide (NO) bioavailability by a reduction of superoxide (O2(•-)) basal level production in the vascular tissue. Male Sprague Dawley rats were given tap water to drink (control group) or tempol (an antioxidant scavenger of superoxide) for 1 week. After 1 week, Nebivolol, at a dose of 3 mg/kg, was injected intravenously to the control group or to the tempol-treated group. Mean arterial pressure, heart rate, and blood pressure variability were evaluated in the control, tempol, nebivolol, and tempol nebivolol groups, as well as, the effect of different inhibitor as Nβ-nitro-l-arginine methyl ester (L-NAME, a Nitric oxide synthase blocker) or glybenclamide, a KATP channel inhibitor. Also, the expression of α,β soluble guanylate cyclase (sGC), phospho-eNOS, and phospho-vasodilator-stimulated phosphoprotein (P-VASP) were evaluated by Western Blot and cyclic guanosine monophosphate (cGMP) levels by an enzyme-linked immunosorbent assay (ELISA) commercial kit assay. We showed that pretreatment with tempol in normotensive rats produces a hypotensive response after nebivolol administration through an increase in the NO bioavailability and sGC, improving the NO/cGMP/protein kinase G (PKG) pathway compared to that of the nebivolol group. We demonstrated that tempol preadministration beneficiates the response of a third-generation beta blocker with eNOS stimulation properties, decreasing the basal uncoupling of eNOS, and improving NO bioavailability. Our results clearly open a possible new strategy therapeutic for treating hypertension.
• Free radical research.Free Radic Res.2014 Feb;48(2):109-18. doi: 10.3109/10715762.2013.845294. Epub 2013 Oct 11.
• Abstract Nebivolol is a third generation beta blocker with endothelial nitric oxide synthase (eNOS) agonist properties. Considering the role of reactive oxygen species (ROS) in the uncoupling of eNOS, we hypothesized that the preadministration of an antioxidant as tempol, could improve the hypotensi
• PMID 24074298

• Neutral endopeptidase (CD10) is abundantly expressed in the epididymis and localized to a distinct population of epithelial cells - Its relevance for CNP degradation.

• Thong A, Müller D, Feuerstacke C, Mietens A, Stammler A, Middendorff R.Author information Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen, 35385 Giessen, Germany.AbstractNeutral endopeptidase (NEP, metallo-endopeptidase EC 3.4.24.11; enkephalinase, neprilysin, CD10, CALLA) represents a major regulator of bioactivity of natriuretic peptides. C-type natriuretic peptide (CNP) is present in high levels in epididymis and seminal plasma. However, detailed expression pattern and CNP-related function of NEP in the epididymis are unknown. Comparison of NEP protein levels in various organs revealed an extremely high expression in human and mouse epididymis. NEP was localized exclusively to apical (luminal) parts of epithelial cells. In man, strong NEP-immunoreactivity was associated with epithelia of efferent ducts and the epididymal duct including stereocilia. Segment-by-segment analysis in mouse revealed a distinct distribution along the epididymal duct. We also found the CNP receptor guanylyl cyclase B (GC-B) in epithelial cells of the epididymal duct. Two different NEP inhibitors decreased CNP degradation and increased CNP/GC-B-induced cGMP production by epididymal membranes, suggesting a functional involvement of NEP. Data indicate an important, previously neglected, role of NEP for regulation of luminal factors in the epididymis and suggest a novel role for CNP/GC-B in the epididymal epithelium, presumably in context of local water balance.
• Molecular and cellular endocrinology.Mol Cell Endocrinol.2014 Jan 25;382(1):234-43. doi: 10.1016/j.mce.2013.09.027. Epub 2013 Oct 4.
• Neutral endopeptidase (NEP, metallo-endopeptidase EC 3.4.24.11; enkephalinase, neprilysin, CD10, CALLA) represents a major regulator of bioactivity of natriuretic peptides. C-type natriuretic peptide (CNP) is present in high levels in epididymis and seminal plasma. However, detailed expression patte
• PMID 24099862

Japanese Journal

• Nitric oxide stimulates IP3 production via a cGMP/ PKG-dependent pathway in rat pancreatic acinar cells

• Moustafa Amira,Sakamoto Kentaro Q,Habara Yoshiaki
• Japanese Journal of Veterinary Research 59(1), 5-14, 2011-02
• … obtained the following results: 1) varying concentrations of an NO donor,sodium nitroprusside (SNP), elevated [IP3]i, 2) this elevation was completely inhibited inthe presence of the soluble guanylyl cyclase (sGC) inhibitor, 1H-[1, 2, 4] oxadiazolo [4, 3-a]quinoxalin-1-one (ODQ), 3) varying concentrations of the cGMP analogue, 8-Br-cGMP, alsoincreased [IP3]i, 4) the cGMP analogue-induced IP3 production was abolished bypretreatment with either a PLC inhibitor, U73122, or a G-protein inhibitor, GP2A, and 5)KT5823, a potent and …
• NAID 120002777846

Related Links

• Guanylyl Cyclase - Basic Neurochemistry - NCBI Bookshelf

Guanylyl cyclase, also termed guanylate cyclase, catalyzes the synthesis of cGMP from GTP in a reaction analogous to that shown in Figure 22-2 for adenylyl cyclase. Two major classes of guanylyl cyclase are known to exist ...

• Guanylyl Cyclases and Signaling by Cyclic GMP

3. Genetic Disorders Associated with Guanylyl Cyclases. The only human diseases mapped to a gene for guanylyl cyclase involve retinal dystrophies. Leber's congenital amaurosis (LCA1), dominant cone-rod ...

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★リンクテーブル★

リンク元	「グアニリルシクラーゼ」「guanyl cyclase」
関連記事	「cyclase」

「グアニリルシクラーゼ」

　　[★]

英

guanylyl cyclase

関

グアニル酸シクラーゼ、グアニルシクラーゼ

「guanyl cyclase」

　　[★]

グアニルシクラーゼ

関

guanylate cyclase、guanylyl cyclase

「cyclase」

　　[★]

シクラーゼ、サイクレース、環化酵素