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)

Atrial natriuretic peptide (ANP) and the closely-related peptides BNP and CNP are highly conserved cardiovascular hormones. They bind to single transmembrane-spanning receptors, triggering receptor-intrinsic guanylyl cyclase activity. The "truncated" type-C natriuretic peptide receptor (NPR-C) has long been called a clearance receptor because it lacks the intracellular guanylyl cyclase domain, though data suggest it might negatively couple to adenylyl cyclase via G(i). Here we report the molecular cloning and characterization of the Xenopus laevis type-C natriuretic peptide receptor (XNPR-C). Analysis confirms the presence of a short intracellular C-terminus, as well as a high similarity to fish and mammalian NPR-C. Injection of XNPR-C mRNA into Xenopus oocytes resulted in expression of high affinity [(125)I]ANP binding sites that were competitively and completely displaced by natriuretic analogs and the unrelated neuropeptide vasoactive intestinal peptide (VIP). Measurement of cAMP levels in mRNA-injected oocytes revealed that XNPR-C is negatively coupled to adenylyl cyclase in a pertussis toxin-sensitive manner. When XNPR-C was co-expressed with PAC(1) receptors for pituitary adenylyl cyclase-activating polypeptide (PACAP), VIP and natriuretic peptides counteracted the cAMP induction by PACAP. These results suggest that VIP and natriuretic peptides can potentially modulate the action of PACAP in cells where these receptors are co-expressed.
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PMID:Paradoxical antagonism of PACAP receptor signaling by VIP in Xenopus oocytes via the type-C natriuretic peptide receptor. 1672 9

We tested the hypothesis that the negative functional effects of natriuretic peptides would be blunted in thyroxine (T4)-induced hypertrophic cardiac myocytes. We also studied the causes of these changes. Ventricular myocytes were obtained from control (n=8) and T4 (0.5 mg/kg/16 days) treated rabbit hearts (n=7). Cell shortening parameters were studied with a video edge detector. We also determined particulate (pGC) and soluble (sGC) guanylyl cyclase activity and cyclic GMP levels. Myocyte function was examined at baseline and after brain natriuretic peptide (BNP 10(-7,-6) M) or C-type natriuretic peptide (CNP 10(-7,-6) M) or zaprinast (cyclic GMP phosphodiesterase inhibitor 10(-6)M) followed by BNP or CNP. Baseline function was similar in control and T4 myocytes. BNP (5.7 +/- 0.2 to 4.3 +/- 0.1%) and CNP (5.7 +/- 0.4 to 4.2 +/- 0.2%) significantly reduced percent shortening in control myocytes. These reductions were not observed with T4 (BNP, 5.7 +/- 0.6 to 5.6 +/- 0.6; CNP, 5.6 +/- 0.4 to 5.5 +/- 0.5). BNP and CNP responded similarly after zaprinast. Baseline cyclic GMP was similar in control and T4, but BNP only increased cyclic GMP in controls. The activity of pGC was similar at baseline in control and T4, but the stimulated activity was significantly lower in T4 myocytes. Both basal and stimulated sGC activity were similar in control and hypertrophic myocytes. These results demonstrated that the ability of natriuretic peptides to reduce ventricular myocyte function was blunted in T4 hypertrophic myocytes. This blunted response was related to the reduced ability of natriuretic peptides to increase cyclic GMP levels due to a reduced stimulated particulate guanylyl cyclase activity.
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PMID:Negative functional effects of natriuretic peptides are attenuated in hypertrophic cardiac myocytes by reduced particulate guanylyl cyclase activity. 1731 51

Retinal blood flow is regulated by local factors. In vitro bioassay experiments give evidence that retinal tissue from different species (dogs, pigs, sheep, cows, rats, and mice) continuously releases a factor lowering tone of isolated retinal arteries. This factor is a general relaxant as it was effective in relaxing different types of vascular as well as nonvascular smooth muscle preparations. This factor is called the retinal relaxing factor (RRF) and its characteristics do not correspond with those of the many well-known vasorelaxants found in retina (i.e., NO, prostanoids, adenosine, ADP, ATP, lactate, glutamate, GABA, taurine, adrenomedullin, CGRP, ANP, BNP, and CNP). This unknown RRF is transferable, hydrophilic, and heat-stable. Its relaxing effect is independent of the presence of the vascular endothelium and of NO-synthase, adenylyl cyclase, guanylyl cyclase, and cyclooxygenase activity. RRF might have a role in hypoxic vasodilation in retinal arteries since hypoxia induces relaxation only when retinal tissue is present. Thus, the RRF pathway is sensitive to changes in oxygen tension and might be a sensitive mechanism for adjusting vascular diameter to retinal oxygen levels. Diminished RRF release might explain the decreased retinal circulation observed in disease with atrophic retina.
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PMID:Control of retinal arterial tone by a paracrine retinal relaxing factor. 1736 60

Exposure to nitrates causes tachyphylaxis to nitric oxide (NO), which reduces the effects of the second messenger cyclic guanosine-3',-5'-monophosphate (cyclic GMP). We tested the hypothesis that prolonged exposure to NO would also blunt the effects of natriuretic peptides. Cardiac myocytes were isolated from control (N=7) and chronic nitroglycerin (patched, N=7) rabbits. Patched animals received a transdermal nitroglycerin patch (0.3mg/h for 5 days). Myocyte function was determined at baseline, after C-type natriuretic peptide (CNP, 10(-8) and 10(-7)M) or brain natriuretic peptide (BNP, 10(-8) and 10(-7)M) or S-nitroso-N-acetyl-penicilliamine (SNAP, a NO donor, 10(-6) and 10(-5)M) followed by KT5823 (a cyclic GMP protein kinase inhibitor, 10(-6)M). Soluble and particulate guanylyl cyclase activities were measured in vitro and phosphoprotein analysis was performed. In control animals, CNP 10(-8)M (5.14+/-0.5%) and 10(-7)M (4.4+/-0.7%) significantly reduced percentage shortening from baseline (6.1+/-1.6%). KT5823 restored percentage shortening to 4.9+/-0.8%. Similar data were obtained with BNP and SNAP. In patched animals, CNP, BNP, SNAP had no significant effects on percentage shortening. The data on maximal rate of shortening and relaxation were consistent with these results. Guanylyl cyclase activities were not different in the control and patched animals. The myocytes from control and patched animals had similar protein phosphorylation patterns. Our data suggested that in addition to NO, the responses to both natriuretic peptides were downregulated after chronic exposure to nitroglycerin, but these effects were not due to changes in either guanylyl cyclase or cyclic GMP protein kinase, suggesting an altered downstream pathway.
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PMID:Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes. 1748 33

Natriuretic peptides (NPs), including atrial, brain and C-type natriuretic peptides (ANP, BNP and CNP), bind two classes of cell surface receptors: the guanylyl cyclase-linked A and B receptors (NPR-A and NPR-B) and the C receptor (NPR-C). The biological effects of NPs have been mainly attributed to changes in intracellular cGMP following their binding to NPR-A and NPR-B. NPR-C does not include a guanylyl cyclase domain. It has been denoted as a clearance receptor and is thought to bind and internalize NPs for ultimate degradation. However, a substantial body of biochemical work has demonstrated the ability of NPR-C to couple to inhibitory G proteins (Gi) and cause inhibition of adenylyl cyclase and activation of phospholipase-C. Recently, novel physiological effects of NPs, mediated specifically by NPR-C, have been discovered in the heart and vasculature. We have described the ability of CNP, acting via NPR-C, to selectively inhibit L-type calcium currents in atrial and ventricular myocytes, as well as in pacemaker cells (sinoatrial node myocytes). In contrast, our studies of the electrophysiological effects of CNP on cardiac fibroblasts demonstrated an NPR-C-Gi-phospholipase-C-dependent activation of a non-selective cation current mediated by transient receptor potential (TRP) channels. It is also known that CNP and BNP have important anti-proliferative effects in cardiac fibroblasts that appear to involve NPR-C. In the mammalian resistance vessels, including mesenteric and coronary arteries, CNP has been found to function as an NPR-C-dependent endothelium-derived hyperpolarizing factor that regulates local blood flow and systemic blood pressure by hyperpolarizing smooth muscle cells. In this review we highlight the role of NPR-C in mediating these NP effects in myocytes and fibroblasts from the heart as well as in vascular smooth muscle cells.
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PMID:Natriuretic peptide C receptor signalling in the heart and vasculature. 1800 79

The natriuretic peptide (NP) family is a seemingly ubiquitous sodium and volume reducing endocrine system of predominantly cardiac origin. Members of the NP system include ANP, BNP, CNP, VNP, their guanylate cyclase (GC)-linked receptors (NPR-A and NPR-B), and clearance receptor (NPR-C). Through the activation of their membrane-bound GC receptors, these small peptides modulate cellular functions that affect both salt and water balance. The elucidation of piscine NP sequences, structure, and functions has steadily advanced over the past 15 years spearheaded by research from Dr. Yoshio Takei's laboratory. The development of these homologous NPs has led to extensive research into both the evolutionary and physiological significance of NPs in fishes. One outcome has been the development of two seemingly disparate hypotheses of NP function; a role in salt excretion, the osmoregulatory hypothesis, versus a role in protecting the heart, the cardioprotective hypotheses. In the osmoregulatory hypothesis NPs are released in response to elevated ambient salinity and inhibit drinking and intestinal uptake of salt, thereby effectively reducing plasma sodium levels. In contrast, the cardioprotective theory depicts NPs acting to prevent debilitating cardiodilation from an excess of either venous or arterial pressure through vasodilation and a reduction of blood volume. These seemingly distinct hypotheses may be elements of a more general regulatory system and certainly require further investigation. Undoubtedly their resolution will not only give us a better perspective of the evolutionary basis of the NP system but will provide us with a greater appreciation of salt and water homeostasis in vertebrates.
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PMID:Comparative physiology of the piscine natriuretic peptide system. 1847 99

The natriuretic peptides (NP) are a group of structurally similar but genetically distinct peptides with many favorable physiological properties that have emerged as important candidates for development of diagnostic tools and therapeutic agents in cardiovascular diseases. The NP family includes atrial natriuretic peptide (ANP, 28AA), urodilatin (INN: Ularitide, 32 AA), B-type natriuretic peptide (BNP, 32AA), C-type natriuretic peptide (CNP, 22AA), and D-type natriuretic peptide (DNP, 38AA). They share common features and exhibit tissue distribution of gene expression as well as functional and pharmacological characteristics. The primary sites of synthesis of the NP are the heart and brain; additional extra cardiac and extra cranial sites include intestine and kidney. Membrane-bound guanyl cyclase-coupled NP receptors (NPR) (A- and B- types) are generally implicated in mediating NP effects via the production of cyclic GMP as the intracellular messenger. NPR-C lacking the guanyl cyclase domain may influence the target cell function through inhibitory guanine nucleotide (Gi) protein, and they likely also act as clearance receptors for circulating peptides. NPs are identified as regulatory diuretic-natriuretic substances responsible for salt and water homeostasis and as hormones lowering blood pressure. This review discusses the essential biochemistry, physiological properties of NP and their manifold functional implications in cardiovascular medicine.
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PMID:Role of natriuretic peptide family in cardiovascular medicine. 1914 42

Atrial (ANP) and C-type (CNP) natriuretic peptide generate physiological effects via selective activation of two closely related membrane receptors with guanylyl cyclase (GC) activity, known as GC-A and GC-B. As yet, however, the discrete roles for ANP/GC-A vs. CNP/GC-B signaling in many mammalian tissues are still poorly understood. We here used receptor affinity labeling and GC assays to characterize comparatively GC-A/GC-B expression and functional activity during rat brain development. The study revealed that GC-B predominates in the developing and GC-A in the adult brain, with regional differences each between cerebral cortex, cerebellum, and brain stem. Whereas GC-A levels nearly continuously increase between embryonal d 18 and adult, GC-B expression in brain is highest and widely distributed around postnatal d 1. The striking perinatal GC-B peak coincides with elevated expression of nestin, a marker protein for neural stem/progenitor cells. Immunohistochemical investigations revealed a cell body-restricted subcellular localization of GC-B and perinatal abundance of GC-B-expressing cells in regions high in nestin-expressing cells. However, and supported by examination of nestin-GFP transgenic mice, GC-B and nestin are not coexpressed in the same cells. Rather, GC-B(+) cells are distinguished by expression of NeuN, an early marker of differentiating neurons. These findings suggest that GC-B(+) cells represent neuronal fate-specific progeny of nestin(+) progenitors and raise the attention to specific and pronounced activities of CNP/GC-B signaling during perinatal brain maturation. The absence of this activity may cause the neurological disorders observed in GC-B-deficient mice.
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PMID:Expression of guanylyl cyclase (GC)-A and GC-B during brain development: evidence for a role of GC-B in perinatal neurogenesis. 1983 75

The aims of the present study were to determine whether natriuretic peptide receptors coupled to guanylate cyclase are present in the neural lobe (NL) of the pituitary and eventually localized on pituicytes and/or on nerve fibers and whether cyclic GMP may be involved in the regulation of vasopressin secretion. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) enhanced cyclic GMP content of NLs in a dose-related fashion, with ED(50) values of about 5 x 10(-8)M, while CNP failed to significantly elevate guanylate cyclase activity. ANP stimulated cyclic GMP accumulation in NLs lacking functional nerve fibers, while it was without significant effect on isolated nerve terminals. In the brain, ANP-enhanced cyclic GMP production was similarly expressed in glial and not in neuronal cultures, although intracellular guanylate cyclase activity (stimulated by sodium nitroprusside) was present in both cell types. Finally, the cell permeant S-bromoguanosine 3':5'-monophosphate GMP failed to change either basal or isoproterenol-stimulated vasopressin secretion from incubated NLs. We conclude that in the NL, as well as in brain tissue cultures, the guanylate cyclase-NP receptor complex (most probably the ANP-A subtype) is localized on pituicytes/filial cells rather than on nerve fibers/cells and that cyclic GMP may not be directly involved in the regulation of vasopressin output from the NL.
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PMID:Evidence for the presence of guanylate cyclase-coupled receptors for atrial natriuretic peptide on pituicytes of the neurohypophysis. 1991 20

Natriuretic peptides (NPs) are a family of structurally related hormone/paracrine factors (ANP, BNP and CNP), which mediate a broad array of physiological effects by interacting with specific guanylyl cyclase receptors (NPR) and have promising therapeutic and clinical applications. NPs are specific for different NPRs and share a common ring structure in which a disulfide bond between two conserved cysteine residues is formed. Residues within the cyclic loop are largely responsible for receptor selectivity. Structural features of free NPs in solution have not been investigated in details even if their characterization would be very useful in order to identify important aspects related to NPs function and receptor selectivity. In light of the above scenario, we carried out a 0.1 micros molecular dynamics investigation of NPs with the aim of providing a high-resolution atomistic view of specific of their conformational ensemble in solution. Our results clearly indicate that NP receptor-bound conformations are not stable solution structure and that induced-fit mechanisms are involved in the formation of NP-NPR complexes. Moreover, in agreement with the current view on strictly relationship between protein dynamics and protein function and activity, it turns out that differences in activity and NPR specificity of CNP and ANP/BNP might be correlated to different amino acid composition of the cyclic loop, propensity to form beta-sheet structures, flexibility patterns, dynamics properties and free conformations explored during the simulations.
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PMID:Molecular dynamics investigation of cyclic natriuretic peptides: dynamic properties reflect peptide activity. 2034 61


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