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)

To investigate the possible relationship of atrial natriuretic factor (ANF) to hypertension, we examined the circulating levels of ANF in 3 patients with pheochromocytomas before surgery, during increase of their blood pressure with surgical manipulation of their tumors, and after surgery when their blood pressures returned to normal. The circulating levels of ANF were increased 2-fold in patients with both extra-adrenal and intra-adrenal pheochromocytomas. In both the intra-adrenal and extra-adrenal patients their ANF levels increased further during surgical manipulation and returned to normal after surgical removal of their respective tumors. Each of these pheochromocytomas was examined and found to have atrial natriuretic receptors that were functional since ANF could enhance the guanylate cyclase - cyclic GMP system two-fold in these pheochromocytomas. We conclude that ANF circulates at higher concentrations in persons with pheochromocytomas and returns to normal with removal of the tumor. In addition, pheochromocytomas contain specific ANF receptors and ANF itself within these tumors.
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PMID:Increased circulating concentration of atrial natriuretic factor in persons with pheochromocytomas. 254 76

Primary cultures of anterior and intermediate pituitary tissues were monitored immunocytochemically for the presence of endocrine and nonendocrine cells and simultaneously tested for their ability to produce cyclic GMP in response to atrial natriuretic factor (ANF). Cells cultured for 3 days and 6 days, in which nonendocrine (vimentin-positive) cells were found to rapidly overgrow the endocrine cells, showed a dramatic elevation in cyclic GMP production stimulated by ANF, with maximum stimulation 300-700% that seen in 1-day cultured cells. Also, ANF-induced accumulation of cyclic GMP in an enriched population of vimentin-positive cells appeared to closely match that triggered in a 3-day culture of anterior pituitary cells, emphasizing the major role played by nonendocrine cells and their ability to synthesize cyclic GMP. In contrast, in the homogeneous population of tumor corticotrophs AtT-20, there was a close relationship between cyclic GMP formation and cell density. It thus appears that contamination of primary cultures of anterior and intermediate pituitary tissues by proliferating nonendocrine cells (mainly fibroblasts), in which ANF-induced accumulation of cyclic GMP may be confused with that of the very secretory cells, leads to overestimation and masking of guanylate cyclase activity of endocrine cells.
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PMID:Stimulation by atrial natriuretic factor of cyclic GMP production in cultured anterior and intermediate pituitary tissues: evidence for a major contribution of proliferating nonendocrine cells. 255 58

The natriuretic effects of atrial peptide hormones have been attributed, at least in part, to their stimulation of guanylate cyclase activity in renal cell membranes. The effects of atrial natriuretic factor (ANF) on stimulation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) accumulation were investigated in cloned human kidney tumor (hKT) cells and parent cells from a human renal tumor epithelial cell line (SK-NEP-1). Human ANF-(99-126) (10(-6)M) stimulated (p less than 0.001) cellular cGMP accumulation in a dose-dependent manner from a basal level of 0.26 +/- 0.04 to 3.73 +/- 0.81 pmol/mg protein/5 mi (mean +/- SEM, n = 13). ANF stimulation of cGMP accumulation was specific, in that high concentrations (10(-6)M) of atriopeptin I [rat ANF-(103-123)], angiotensin II, arginine vasopressin, and amiloride (10(-4)M) did not increase basal cGMP. Amiloride (10(-4)M) enhanced (p less than 0.01, n = 6) the ANF stimulation of cGMP accumulation (1.24 +/- 0.39 pmol/mg protein/5 min), particularly at low doses of ANF (10(-10)M) where stimulation by ANF without amiloride (0.34 +/- 0.08 pmol/mg protein/5 min) was barely distinguishable from a basal level (0.19 +/- 0.02 pmol/mg protein/5 min) of cGMP accumulation. The stimulatory effect of ANF (1.59 +/- 0.07 pmol/mg protein/5 min) was attenuated (0.75 +/- 0.06 pmol/mg protein/5 min, p less than 0.01, n = 6) by preincubation of the cells with pertussis toxin but not by cholera toxin. ANF (4.56 +/- 0.93 pmol/mg protein/5 min, n = 8) did not affect cAMP accumulation (4.32 +/- 0.98 pmol/mg protein/5 min) in hKT cells. This is the first report of an ANF responsive human renal cell line, and its use should facilitate investigation of ANF-receptor interactions.
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PMID:Atrial natriuretic factor effects on cyclic nucleotides in a human renal cell line. 256 5

Adenylate and guanylate cyclase activities were demonstrated in R3230AC rat mammary adenocarcinomas by electron microscopic cytochemistry. Adenylate (AC) and guanylate (GC) cyclases were detected on plasma membrane of tumor epithelial cells, but not on fibroblasts and endothelial cells in the perivascular space. Both AC and GC activities were enriched in tumor epithelial cells at the periphery of the tumor lobular parenchyma rather than in cells in central core of the lobular parenchyma. Furthermore, the tumor cell plasma membranes facing the connective tissue stroma were in paucity or devoid of either enzyme activity. These heterogeneous distributions of both AC and GC among tumor epithelia suggest that R3230AC epithelial cells in different parts of the tumor mass may vary significantly in their regulation of cellular physiology.
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PMID:Heterogeneous localization of adenylate and guanylate cyclases in R3230AC rat mammary adenocarcinoma cells. 286 31

Native rat atrial natriuretic peptide (NANP) was shown to bind with high affinity and to increase intracellular levels of cGMP in cultured rat Leydig tumor cells. A linear analog of NANP which lacks the disulfide-linked bridge structure also bound with high affinity but did not increase levels of intracellular cGMP or antagonize the increase of this cyclic nucleotide by NANP. These data are consistent with the existence of two functional subpopulations of ANP receptors on cultured rat Leydig tumor cells; one which is capable of activating guanylate cyclase and one which is not linked to this enzyme.
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PMID:Functional multiplicity of atrial natriuretic peptide receptors on cultured rat Leydig tumor cells. 289 47

A highly differentiated thyroid cell line (FR-RL) was compared with a less differentiated (FR-T Cl1) and an undifferentiated (1-5G) cell line. FR-TL is modulated in vivo and in vitro by thyrotropin and has the lowest adenylate cyclase and guanylate cyclase and the highest phosphodiesterase activities. In contrast, 1-5G tumor cells do not respond to thyrotropin and have the highest adenylate cyclase guanylate cyclase and lowest hydrolyzing enzyme activities. Intermediate enzyme activities were found in FR-T Cl1 cells. The differences between the two normal rat thyroid cell lines are not due to differences in the composition of the growth medium.
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PMID:Cyclic nucleotide metabolism in differentiated and undifferentiated epithelial thyroid cells in culture. 611 52

The cyclic GMP content of diethylstilbestrol-induced renal tumors in the male golden hamster was increased nearly 130-fold over that in kidney from control animals. Cyclic GMP in tumors was 91.80 +/- 19.18 pmoles cyclic GMP/mg protein compared to 0.72 +/- 0.07 in control kidneys. Cyclic AMP in tumors was also increased over control, however, to a much lesser degree (2.7-fold). In control kidneys, 84.6% of homogenate guanylate cyclase activity was recovered in the 100,000 X g supernatant fraction. Total homogenate guanylate cyclase activity from diethylstilbestrol-induced renal tumors was increased 5.5-fold over that in control kidneys and only 8.1% was associated with the 100,000 X g supernatant fraction. Neither the soluble or particulate guanylate cyclase from renal tumors could be activated by nitric oxide. The unresponsiveness of tumor guanylate cyclase to nitric oxide was independent of the cation cofactor, and not due to a shift in the dose response curve for nitric oxide. Responsiveness to nitric oxide was not restored by thiols, sugars, other proteins, or hemoglobin. Basal cyclic AMP formation by soluble guanylate cyclase from renal tumors was dramatically increased over that observed in control kidneys, and could not be increased further by nitric oxide. This is the first study of cyclic GMP and guanylate cyclase in a primary estrogen-induced tumor. The possibility that the changes observed in guanylate cyclase from diethylstilbestrol-induced renal tumors are related to in vivo activation of the enzyme by epoxide metabolites of diethylstilbestrol is discussed.
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PMID:Alterations in the subcellular distribution of Guanylate cyclase and its responsiveness to nitric oxide in diethylstilbestrol-induced renal tumors. 612 81

Several lines of evidence suggest that nitric oxide (NO), generated through nitric oxide synthase (NOS) by cleavage of terminal guanidino nitrogen from L-arginine, mediates tumor cell killing by mononuclear phagocytes. Natural killer (NK) cells are cytotoxic effector cells that lyse a variety of tumor and virus-infected cells in a MHC-unrestricted manner. NK cells cultured with interleukin 2 proliferate and acquire the ability to lyse a wide range of targets, including NK-resistant tumor cells (LAK activity). The present study was designed to investigate whether a NOS pathway exists in fresh or IL-2-activated NK cells and to assess the importance of NO synthesis in their activation and cytotoxic functions. NKR-P1 triggering, which is known to induce NK cell activation and mediate reverse ADCC, was able to induce arginine metabolism with consequent increase of nitrite and citrulline levels. Moreover, stimulated NO synthesis leads to guanylate cyclase activity with consequent cGMP generation. We also report that cytotoxic activities of fresh or IL-2-activated NK cells appear to be dependent on arginine levels in medium. Tumoricidal activity of both these effector cells, assessed against YAC-1 and P815 target cells, respectively, was indeed significantly reduced when cytotoxic assays were performed in arginine-free medium or in the presence of the L-arginine analog L-N-monomethyl-arginine, which inhibits nitroxide formation from L-arginine. Normal levels of cytotoxic activities could be restored by addition of exogenous L-arginine. NO generation by NK and LAK cells, determined as nitrite, citrulline, and cGMP synthesis, correlated well with their cytotoxic activities. Moreover, NOS activity gradually increased during the LAK generation and correlated well with the increasing capability of IL-2-activated NK cells to lyse NK-resistant targets, such as P815.
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PMID:Induction of the nitric oxide-synthesizing pathway in fresh and interleukin 2-cultured rat natural killer cells. 751 50

Guanosine 5'-(gamma-thio)triphosphate (GTP gamma S) exhibited a modulatory role in the catalytic activation of guanylate cyclase-A/atrial natriuretic factor receptor (GC-A/ANF-R) in the plasma membrane preparations of murine Leydig tumor (MA-10) cells. Both atrial natriuretic factor (ANF) and GTP gamma S synergistically stimulated the guanylate cyclase (GC) activity of GC-A/ANF-R in a dose- and time-related manner. Other nucleotides and their analogs such as ATP, adenosine 5'-(gamma-thio)triphosphate, adenosine 5'-(beta,gamma-imino)triphosphate, GDP, and guanosine 5'-(2-O-thiodiphosphate) (100 microM each) did not show any discernible effect on GC catalytic activity of GC-A/ANF-R. A significant stimulation of GC activity was observed in the presence of mastoparan, AlF4-, and benzalkonium chloride. The saturation binding assay of [35S]GTP gamma S showed the dissociation constant (Kd) of 2.3 x 10(-9) M and the binding capacity (Bmax) of 76 pmol/mg protein in the plasma membrane preparations of MA-10 cells. ANF increased the [35S]GTP gamma S-binding capacity, however, without affecting its affinity constant. Pretreatment of plasma membranes with antibodies against Gs alpha subunit attenuates the GTP gamma S-stimulated GC activity, whereas antibodies against Gi alpha subunit enhanced the stimulatory effect of GTP gamma S on GC catalytic activity of GC-A/ANF-R. However, the antibodies against Go alpha subunit did not show any effect on GC activity. These results provide the evidence that both Gs and Gi subunits of G-proteins seem to be involved in the regulation of GC catalytic activity of GC-A/ANF-R in the plasma membranes of MA-10 cells.
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PMID:Catalytic activation of guanylate cyclase/atrial natriuretic factor receptor by combined effects of ANF and GTP gamma S in plasma membranes of Leydig tumor cells: involvement of G-proteins. 784 Jun 42

Mastoparan potently stimulated catalytic activity of guanylate cyclase-coupled atrial natriuretic factor receptor (GC-A/ANF-R), both in the plasma membranes and intact Leydig tumor (MA-10) cells. In plasma membrane preparations, a maximum of 5-fold GC catalytic activity was stimulated by 100 microM mastoparan and the half maximum stimulation (EC50) was achieved at 40 microM concentration. Mastoparan potentiated GC activity by more than 40%, above the level, stimulated by ANF. Mas 7, an active analog of mastoparan, stimulated the GC activity in a similar manner to mastoparan whereas Mas 17, an inactive analog, did not enhance GC activity. In membranes prepared from mastoparan-treated intact MA-10 cells, GC catalytic activity was enhanced by more than 4-fold as compared with untreated control cells. Pretreatment of membranes with either anti-Gs alpha or anti-Gi alpha antibodies had no effect on mastoparan-stimulated GC activity, however, anti-Go alpha antibodies inhibited the stimulatory effect of mastoparan by almost 50%. Agents known to modulate the effect of mastoparan such as EGTA (Ca2+ chelator), W7 (calmodulin inhibitor) and staurosporine (protein kinase C inhibitor) had no effect on the mastoparan-stimulated GC activity. Mastoparan enhanced the ANF-stimulated GC activity in detergent solubilized membrane preparations without a significant change in ANF-binding capacity. The data establish a role for mastoparan in the ANF-dependent stimulation of GC-A/ANF-R catalytic activity, both in the plasma membrane preparations and intact Leydig tumor (MA-10) cells. Furthermore, these findings provide new evidence that mastoparan (isolated from wasp venom) potently stimulates guanylate cyclase activity of GC-A/ANF-R by activating G-proteins.
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PMID:Modulation of guanylate cyclase-coupled atrial natriuretic factor receptor activity by mastoparan and ANF in murine Leydig tumor cells: role of G-proteins. 794 43


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