Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the principal loci involved in the regulatory action of atrial and brain natriuretic peptides (ANP and BNP) is guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), whose ligand-binding efficiency and GC catalytic activity vary remarkably in different target cells and tissues. In its mature form, NPRA resides in the plasma membrane and contains an extracellular ligand-binding domain, a single transmembrane region, and the intracellular protein kinase-like homology domain (KHD) and guanylyl cyclase (GC) catalytic domain. NPRA is a dynamic cellular macromolecule that traverses through different compartments of the cell through its lifetime. Binding of ligand to NPRA triggers a complex array of signal transduction events and accelerates the endocytosis. The endocytic transport is important in regulating signal transduction, formation of specialized signaling complexes, and modulation of specific components of internalization events. The present review describes the experiments which reveal the internalization of ligand-receptor complexes of NPRA, receptor trafficking and recycling, and delivery of both ligand-receptor molecules into subcellular compartments. The ligand-receptor complexes of NPRA are finally degraded within the lysosomes. The experimental evidence provides a consensus forum, which establishes the endocytosis, cellular trafficking, sequestration, and metabolic processing of ANP/NPRA complexes in the intact cells. The discussion is afforded to address the experimental insights into the mechanisms that cells utilize in modulating the delivery and metabolic processing of ligand-bound NPRA into the cell interior.
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PMID:Internalization and trafficking of guanylyl cyclase/natriuretic peptide receptor-A. 1591 Oct 67

Cyclic GMP (cGMP)-dependent protein kinase II (Prkg2, cGK II) was identified as a potential target of the progesterone receptor (Nr3c3) in the mouse ovary based on microarray analyses. To document this further, the expression patterns of cGK II and other components of the cGMP signaling pathway were analyzed during follicular development and ovulation using the pregnant mare serum gonadotropin (PMSG)-human chorionic gonadotropin (hCG)-primed immature mice. Levels of cGK II mRNA were low in ovaries of immature mice, increased 4-fold in response to pregnant mare serum gonadotropin and 5-fold more within 12 h after hCG, the time of ovulation. In situ hybridization localized cGK II mRNA to granulosa cells and cumulus oocyte complexes of periovulatory follicles. In progesterone receptor (PR) null mice, cGK II mRNA was reduced significantly at 12 h after hCG in contrast to heterozygous littermates. In primary granulosa cell cultures, cGK II mRNA was induced by phorbol 12-myristate 13-acetate enhanced by adenoviral expression of PR-A and blocked by RU486 and trilostane. PR-A in the absence of phorbol 12-myristate 13-acetate was insufficient to induce cGK II. Expression of cGK I (Prkg1) was restricted to the residual tissue and not regulated by hormones. Guanylate cyclase-A (Npr1; GC-A) mRNA expression increased 6-fold by 4 h after hCG treatment in contrast to pregnant mare serum gonadotropin alone and was localized to granulosa cells of preovulatory follicles. Collectively, these data show for the first time that cGK II (not cGK I) and GC-A are selectively induced in granulosa cells of preovulatory follicles by LH- and PR-dependent mechanisms, thereby providing a pathway for cGMP function during ovulation.
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PMID:Cyclic guanosine 5'-monophosphate-dependent protein kinase II is induced by luteinizing hormone and progesterone receptor-dependent mechanisms in granulosa cells and cumulus oocyte complexes of ovulating follicles. 1621 Mar 44

Natriuretic peptides (NPs) may work as neuromodulators through their associated receptors [NP receptors (NPRs)]. By immunocytochemistry, we showed that NPR-A and NPR-B were expressed abundantly on both ON-type and OFF-type bipolar cells (BCs) in rat retina, including the dendrites, somata, and axon terminals. Whole-cell recordings made from isolated ON-type BCs further showed that brain natriuretic peptide (BNP) suppressed GABAA receptor-, but not GABAC receptor-, mediated currents of the BCs, which was blocked by the NPR-A antagonist anantin. The NPR-C agonist c-ANF [des(Gln18, Ser19, Gln20, Leu21, Gly22)ANF(4-23)-NH2] did not suppress GABAA currents. The BNP effect on GABAA currents was abolished with preincubation with the pGC-A/B antagonist HS-142-1 but mimicked by application of 8-bromoguanosine-3',5'-cyclomonophosphate. These results suggest that elevated levels of intracellular cGMP caused by activation of NPR-A may mediate the BNP effect. Internal infusion of the cGMP-dependent protein kinase G (PKG) inhibitor KT5823 essentially blocked the BNP-induced reduction of GABAA currents. Moreover, calcium imaging showed that BNP caused a significant elevation of intracellular calcium that could be caused by increased calcium release from intracellular stores by PKG. The BNP effect was blocked by the ryanodine receptor modulators caffeine, ryanodine, and ruthenium red but not by the IP3 receptor antagonists heparin and xestospongin-C. Furthermore, the BNP effect was abolished after application of the blocker of endoplasmic reticulum Ca2+-ATPase thapsigargin and greatly reduced by the calmodulin inhibitors W-7 and calmidazolium. We therefore conclude that the increased calcium release from ryanodine-sensitive calcium stores by BNP may be responsible for the BNP-caused GABAA response suppression in ON-type BCs through stimulating calmodulin.
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PMID:Modulation by brain natriuretic peptide of GABA receptors on rat retinal ON-type bipolar cells. 1640 67

The cardiac hormone atrial natriuretic peptide (ANP) signals via interaction with a plasma membrane receptor, which has guanylyl cyclase (GC) activity and is referred to as GC-A. Desensitization of GC-A is thought to represent a physiologically important regulatory mechanism, but the signaling pathways implicated and cell type-specific effects are still poorly understood. Here we demonstrate that sustained exposure to either ANP itself or the bioactive lipid lysophosphatidic acid (LPA) elicits GC-A desensitization in MA-10 Leydig cells. Both reactions show similar kinetics and evoke equal decreases (by 40%) in GC-A hormone responsiveness. Homologous (ANP induced) desensitization, in which cGMP is generated as second messenger, is blocked by distinct cAMP-dependent protein kinase [protein kinase A (PKA)] inhibitors, H 89, and Rp-8-CPT-cAMPs, providing evidence that PKA mediates the reaction. Accordingly, the ANP/cGMP-elicited effects are mimicked by a cAMP analog, 8-bromo-cAMP. The LPA-induced (heterologous) desensitization is not blocked by PKA inhibition, indicating a different signaling pathway. LPA, but not ANP, enhances ERK phosphorylation and induces cell rounding together with a dramatic reorganization of actin filaments. Consistent with the identification of LPA receptor (LPA2 and LPA3) gene expression, the findings are indicative of LPA receptor-mediated reactions. This study demonstrates for the first time coexistence of homologous and heterologous desensitization of GC-A in the same cell type, reveals that these reactions are mediated by different pathways, and identifies a novel cross talk between phospholipid and natriuretic peptide signaling. The morphoregulatory activities exerted by LPA suggest a crucial role for Leydig cell physiology.
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PMID:Homologous and lysophosphatidic acid-induced desensitization of the atrial natriuretic peptide receptor, guanylyl cyclase-A, in MA-10 leydig cells. 1652 39

Human fat cell lipolysis was considered until recently to be an exclusive cAMP/protein-kinase A (PKA)-regulated metabolic pathway under the control of catecholamines and insulin. Moreover, exercise-induced lipid mobilization in humans was considered to mainly depend on catecholamine action and interplay between fat cell beta- and alpha2-adrenergic receptors controlling adenylyl cyclase activity and cAMP production. We have recently demonstrated that natriuretic peptides stimulate lipolysis and contribute to the regulation of lipid mobilization in humans. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) stimulate lipolysis in human isolated fat cells. Activation of the adipocyte plasma membrane type A guanylyl cyclase receptor (NPR-A), increase in intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) levels and activation of hormone-sensitive lipase mediate the action of ANP. ANP does not modulate cAMP production and PKA activity. Increment of cGMP induces the phosphorylation of hormone-sensitive lipase and perilipin A via the activation of a cGMP dependent protein kinase-I (cGK-I). Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans. Physiological relevance of the ANP-dependent pathway was demonstrated in young subjects performing physical exercise. ANP plays a role in conjunction with catecholamines in the control of exercise-induced lipid mobilization. This pathway becomes of major importance when subjects are submitted to chronic treatment with a beta-blocker. Oral beta-adrenoceptor blockade suppresses the beta-adrenergic component of catecholamine action in fat cells and potentiates exercise-induced ANP release by the heart. These findings may have several implications whenever natriuretic peptide secretion is altered such as in subjects with left ventricular dysfunction, congestive heart failure and obesity.
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PMID:[Natriuretic peptides: a new lipolytic pathway in human fat cells]. 1659 2

Evidence suggests that functional atrial natriuretic peptide (ANP) receptors occur in surface gastric mucosal epithelial cells. To evaluate functional aspects of ANP in a model of these cells we examined the expression of natriuretic peptide receptors (NPR) subtypes A and C in the non-transformed rat gastric mucosal epithelial cell line RGM1. Transcripts for NPR-A and NPR-C were detected in RGM1 cells by RT-PCR. However, only NPR-C protein was detected by Western blot and immunohistochemical analyses. Specific saturable binding of (125)I-ANP to RGM1 cells revealed a single class of high affinity binding sites (K (d) = 208 +/- 71pM, B (max) = 110,000 +/- 14,000 sites/cell, Hill coefficient = 0.97 +/- 0.05). ANP (IC(50) 130 +/- 47pM), BNP (IC(50) 716 +/- 26 pM), CNP (IC(50) 356 +/- 85pM) and C-ANP (IC(50) 134 +/- 13pM), a specific ligand for NPR-C, effectively displaced (125)I-ANP binding. Cross-linking of (125)I-ANP to cells labeled predominantly a protein of 66,000 Da. These data suggest that (125)I-ANP binding was primarily to NPR-C. ANP and C-ANP inhibited forskolin- and prostaglandin E(2) (PGE(2))-stimulated cAMP in a PTx-sensitive fashion. PGE(2), transforming growth factor-+/-1 (TGF-+/-1), forskolin, 8-bromo-cyclic AMP, and phorbol-12-myristate-13-acetate (PMA) caused a dose-dependent decrease in specific (125)I-ANP binding, whereas epidermal growth factor (EGF), 8-bromo-cyclic GMP and 4+/--phorbol didecanoate had no effect. PGE(2), forskolin, TGF-+/-1 and PMA significantly decreased (125)I-ANP B (max) values, NPR-C protein and steady-state NPR-C transcript levels. H89, a protein kinase A inhibitor, blocked the reduction of NPR-C mRNA produced by both forskolin and PGE(2.) GF109203X, a protein kinase C inhibitor, abolished the PMA-induced decrease in NPR-C transcripts but only partially blocked that produced by TGF-+/-1. RGM1 cells exhibited a dose-dependent decrease in both DNA synthesis and cell proliferation when cultured in the presence of ANP or C-ANP. These findings indicate that RGM1 cells express functional NPR-C receptors that can influence RGM1 cell proliferation and are down-regulated by PGE(2) and TGF-+/-1.
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PMID:Identification, regulation and anti-proliferative role of the NPR-C receptor in gastric epithelial cells. 1678 90

Dopamine (DA) and atrial natriuretic factor (ANF) share a number of physiological effects. We hypothesized that ANF and the renal dopaminergic system could interact and enhance the natriuretic and diuretic effects of the peptide. We have previously reported that the ANF-stimulated DA uptake in renal tubular cells is mediated by the natriuretic peptide type-A receptor (NPR-A). Our aim was to investigate the signaling pathways that mediate ANF effects on renal 3H-DA uptake. Methylene blue (10 microM), an unspecific inhibitor of guanylate cyclase (GC), blunted ANF elicited increase of DA uptake. ODQ (10 microM) a specific inhibitor of soluble GC, did not modify DA uptake and did not reverse ANF-induced increase of DA uptake; then the participation of nitric oxide-dependent pathways must be discarded. The second messenger was the cGMP since the analogous 125 microM 8-Br-cGMP mimicked ANF effects. The specific inhibitor of the protein kinase G (PKG), KT 5823 (1 microM) blocked ANF effects indicating that PKG is involved. We examined if ANF effects on DA uptake were able to modify Na+, K+ -adenosine triphosphatase (Na+, K+ -ATPase) activity. The experiments were designed by means of inhibition of renal DA synthesis by carbidopa and neuronal DA uptake blocked by nomifensine. In these conditions renal Na+, K+ -ATPase activity was increased, in agreement with the decrease of DA availability. When in similar conditions, exogenous DA was added to the incubation medium, the activity of the enzyme tended to decrease, following to the restored availability of DA. The addition of ANF alone had similar effects to the addition of DA on the sodium pump, but when both were added together, the activity of Na(+), K(+)-ATPase was decreased. Moreover, the extraneuronal uptake blocker, hydrocortisone, inhibited the latter effect. In conclusion, ANF stimulates extraneuronal DA uptake in external cortex tissues by activation of NPR-A receptors coupled to GC and it signals through cGMP as second messenger and PKG. Dopamine and ANF may achieve their effects through a common pathway that involves reversible deactivation of renal tubular Na+, K+ -ATPase activity. This mechanism demonstrates a DA-ANF relationship involved in the modulation of both decreased sodium reabsorption and increased natriuresis.
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PMID:Signaling pathways involved in atrial natriuretic factor and dopamine regulation of renal Na+, K+ -ATPase activity. 1700 63

Several studies show that C-type natriuretic peptide (CNP) has a modulatory role in the digestive system. CNP administration reduces both jejunal fluid and bile secretion in the rat. In the present study we evaluated the effect of CNP on amylase release in isolated pancreatic acini as well as the receptors and intracellular pathways involved. Results showed that all natriuretic peptide receptors were expressed not only in the whole pancreas but also in isolated pancreatic acini. CNP stimulated amylase secretion with a concentration-dependent biphasic response; maximum release was observed at 1 pM CNP, whereas higher concentrations gradually attenuated it. The response was mimicked by a selective natriuretic peptide receptor (NPR-C) agonist and inhibited by pertussis toxin, strongly supporting NPR-C receptor activation. CNP-evoked amylase release was abolished by U-73122 (PLC inhibitor) and 2-aminoethoxydiphenyl borate (2-APB) [an inositol 1,4,5-triphosphate (IP(3)) receptor antagonist], partially inhibited by GF-109203X (PKC inhibitor), and unaltered by ryanodine or protein kinase A (PKA) and protein kinase G (PKG) inhibitors. Phosphoinositide hydrolysis was enhanced by CNP at all concentrations and abolished by U-73122. At 1 and 10 pM, CNP did not affect cAMP or guanosine 3',5'-cyclic monophosphate (cGMP) levels, but at higher concentrations it increased cGMP and diminished cAMP content. Present findings show that CNP stimulated amylase release through the activation of NPR-C receptors coupled to the PLC pathway and downstream effectors involved in exocytosis. The attenuation of amylase release was likely related to cAMP reduction. The augmentation in cGMP supports activation of NPR-A/NPR-B receptors probably involved in calcium influx. Present findings give evidence that CNP is a potential direct regulator of pancreatic function.
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PMID:C-type natriuretic peptide enhances amylase release through NPR-C receptors in the exocrine pancreas. 1770 53

Natriuretic peptides (NPs) and their receptors (NPRs) are expressed in the heart, but their effects on myocyte function are poorly understood. Because NPRs are coupled to synthesis of cGMP, an activator of the sarcolemmal Na(+)-K(+) pump, we examined whether atrial natriuretic peptide (ANP) regulates the pump. We voltage clamped rabbit ventricular myocytes and identified electrogenic Na(+)-K(+) pump current (arising from the 3:2 Na(+):K(+) exchange and normalized for membrane capacitance) as the shift in membrane current induced by 100 micromol/l ouabain. Ten nanomoles per liter ANP stimulated the Na(+)-K(+) pump when the intracellular compartment was perfused with pipette solutions containing 10 mmol/l Na(+) but had no effect when the pump was at near maximal activation with 80 mmol/l Na(+) in the pipette solution. Stimulation was abolished by inhibition of cGMP-activated protein kinase with KT-5823, nitric oxide (NO)-activated guanylyl cyclase with 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ), or NO synthase with N(G)-nitro-L-arginine methyl ester (L-NAME). Since synthesis of cGMP by NPR-A and NPR-B is not NO dependent or ODQ sensitive, we exposed myocytes to AP-811, a highly selective ligand for the NPR-C "clearance" receptor. It abolished ANP-induced pump stimulation. Conversely, the selective NPR-C agonist ANP(4-23) reproduced stimulation. The stimulation was blocked by l-NAME. To examine NO production in response to ANP(4-23), we loaded myocytes with the NO-sensitive fluorescent dye diacetylated diaminofluorescein-2 and examined them by confocal microscopy. ANP(4-23) induced a significant increase in fluorescence, which was abolished by L-NAME. We conclude that NPs stimulate the Na(+)-K(+) pump via an NPR-C and NO-dependent pathway.
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PMID:Natriuretic peptides stimulate the cardiac sodium pump via NPR-C-coupled NOS activation. 1827 21

The ATP-sensitive potassium (K(ATP)) channel is a key molecule involved in glucose-stimulated insulin secretion. The activity of this channel regulates beta-cell membrane potential, glucose- induced [Ca(2+)](i) signals, and insulin release. In this study, the rapid effect of physiological concentrations of 17beta-estradiol (E2) on K(ATP) channel activity was studied in intact beta-cells by use of the patch-clamp technique. When cells from wild-type (WT) mice were used, 1 nm E2 rapidly reduced K(ATP) channel activity by 60%. The action of E2 on K(ATP) channel was not modified in beta-cells from ERalpha-/- mice, yet it was significantly reduced in cells from ERbeta-/- mice. The effect of E2 was mimicked by the ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN). Activation of ERbeta by DPN enhanced glucose-induced Ca(2+) signals and insulin release. Previous evidence indicated that the acute inhibitory effects of E2 on K(ATP) channel activity involve cyclic GMP and cyclic GMP-dependent protein kinase. In this study, we used beta-cells from mice with genetic ablation of the membrane guanylate cyclase A receptor for atrial natriuretic peptide (also called the atrial natriuretic peptide receptor) (GC-A KO mice) to demonstrate the involvement of this membrane receptor in the rapid E2 actions triggered in beta-cells. E2 rapidly inhibited K(ATP) channel activity and enhanced insulin release in islets from WT mice but not in islets from GC-A KO mice. In addition, DPN reduced K(ATP) channel activity in beta-cells from WT mice, but not in beta-cells from GC-A KO mice. This work unveils a new role for ERbeta as an insulinotropic molecule that may have important physiological and pharmacological implications.
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PMID:Rapid regulation of K(ATP) channel activity by 17{beta}-estradiol in pancreatic {beta}-cells involves the estrogen receptor {beta} and the atrial natriuretic peptide receptor. 1985 88


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