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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We earlier showed that the diacylglycerol (DG) lipase inhibitor, RHC 80267, increased the steady-state level of DG and inhibited the release of arachidonic acid (AA) in carbamylcholine (CCh)-stimulated pancreatic minilobules (J. F. Dixon and L. E. Hokin, (1984) J. Biol. Chem. 259, 14418-14425). There was no effect on phospholipid metabolism. We have now investigated the effect of RHC 80267 on CCh-stimulated formation of inositol monophosphate formation, cGMP formation, and amylase release. CCh (10 microM) increased cGMP formation by approximately 20-fold, and this response was inhibited 55-75% by RHC 80267 (75-100 microM). RHC 80267 had no effect on either nitroprusside- or calcium ionophore-stimulated cGMP formation, arguing against a direct inhibition of guanylate cyclase by RHC 80267. Arachidonic acid, the release of which is inhibited by RHC 80267, neither stimulated cGMP formation nor reversed the effect of RHC 80267 on CCh-stimulated cGMP formation. This suggests, but does not prove, that the rise in cGMP in response to CCh is not due to an increase in AA as has been suggested. Both phorbol myristate acetate (25 nM) and the DG kinase inhibitor R 59022 (10 microM) inhibited CCh-stimulated cGMP formation by 40%. RHC 80267 also inhibited CCh-stimulated inositol phosphate accumulation and amylase release by 60 and 40%, respectively. The data suggest that the inhibition of CCh-stimulated cGMP formation and other muscarinic responses by RHC 80267 is probably the result of feedback inhibition of the cholinergic receptor via activation of protein kinase C by the elevated DG.
...
PMID:Inhibitors of diacylglycerol lipase and diacylglycerol kinase inhibit carbamylcholine-stimulated responses in guinea pig pancreatic minilobules. 244 62

The combination of carbachol and 20 mM K+ greatly stimulates phosphoinositide hydrolysis in rat cerebral cortical slices. This response was inhibited by sodium nitroprusside, an activator of guanylate cyclase which elevated guanosine 3',5'-monophosphate (cyclic GMP) levels. 8-Bromocyclic GMP and the phorbol ester phorbol myristate acetate (PMA) also inhibited phosphoinositide hydrolysis, and the inhibitory effect of PMA was additive with that of sodium nitroprusside. As guanylate cyclase is Ca2+-dependent this inhibition of phosphoinositide hydrolysis by cyclic GMP may serve as a feedback modulator of the production of inositol phosphates and the ensuing rise of intracellular calcium.
...
PMID:Sodium nitroprusside and guanosine 3',5'-monophosphate (cyclic GMP) inhibit stimulated phosphoinositide hydrolysis in rat cerebral cortical slices. 254 29

1. Retinas from channel catfish were dissociated and the cells maintained in culture. Horizontal cells that normally receive input from cone photoreceptors were identified. The conductance of the electrical junction formed between a pair of 'cone' horizontal cells was measured by controlling the membrane voltage of each cell with a voltage clamp maintained through either a micropipette or a patch pipette. The two techniques yielded similar results. 2. Transjunctional current was measured while transjunctional voltage was stepped to values between +/- 60 mV. The current (measured 5 ms after a step) was proportional to voltage over the range tested. For steps to voltages greater than +/- 45 mV, the current exhibited a slight time-dependent decline. 3. Dopamine decreased junctional conductance in a dose-dependent fashion. A 50% reduction was obtained with 10 nM-dopamine. The D1 agonist fenoldopam (100 nM) also decreased junctional conductance. The uncoupling produced by either agent was rapid and reversible. 4. The introduction of 100 microM-cyclic AMP into one cell of a pair decreased junctional conductance by, on average, 40%. Forskolin (1-10 microM), an activator of adenylate cyclase, decreased junctional conductance 50-90%. 5. The introduction of 80 microM-cyclic GMP into one cell of a pair decreased junctional conductance by, on average, 40%. Nitroprusside (1-10 microM), an activator of guanylate cyclase, reduced junctional conductance 40-65%. 6. The introduction of a peptide inhibitor specific for the cyclic AMP-dependent protein kinase reversed a decrease in junctional conductance produced by superfusion with either dopamine (1 microM), fenoldopam (100 nM) or forskolin (5-10 microM). 7. Intracellular Ca2+ concentration was measured with the fluorescent indicator Fura-2. The intracellular Ca2+ concentration was increased by activation of a Ca2+ current. Junctional conductance remained constant as the internal Ca2+ concentration changed from 100 to 700 nM. 8. Intracellular pH was measured with the fluorescent indicator bis-carboxyethylcarboxyfluorescein. The application of acetate (2.5 mM) reduced intracellular pH by 0.2-0.3 units and decreased junctional conductance by approximately 50%. A subsequent application of fenoldopam did not alter intracellular pH, but decreased junctional conductance by more than 50%. 9. The sensitivity of the junctional conductance between isolated horizontal cells to dopamine is consistent with dopamine having a direct effect on coupling in intact retina. Dopamine regulates the activity of a cyclic AMP-dependent protein kinase which in turn modulates junctional conductance. Changes in intracellular pH and Ca2+ concentration are not involved in mediating the effect of dopamine on coupling. Cyclic GMP and intracellular pH may participate in regulatory pathways independent of that used by cyclic AMP.
...
PMID:Modulation of an electrical synapse between solitary pairs of catfish horizontal cells by dopamine and second messengers. 255 70

The objective of this study was to investigate the effects of 4 beta-phorbol 12-myristate 13-acetate (4 beta-PMA)--a potent activator of protein kinase C--on the responsiveness of mouse Leydig cells to stimulation with rat atriopeptin II (rAP-II). We report that, in these cells, the stimulation of testosterone production by rAP-II could be inhibited in a dose-dependent manner by 4 beta-PMA (1-200 nM). In contrast, the basal steroidogenesis was stimulated 2-fold by 4 beta-PMA. There was no inhibition of testosterone production when the cells were stimulated with 8-bromo cyclic GMP (8Br-cGMP) in the presence of 4 beta-PMA. Furthermore, addition of 4 beta-PMA resulted in a marked reduction in the amount of cGMP accumulated in response to rAP-II stimulation. 4 alpha-Phorbol 12-myristate 13-acetate (4 alpha-PMA) was found to have no effect at all. The inhibitory effect of 4 beta-PMA on steroidogenesis could be completely reversed by the addition of 0.25 mM 3-isobutyl 1-methylxanthine (IBMX), a phosphodiesterase inhibitor. Also, the 4 beta-PMA-induced lowering of cGMP content could be partially reversed by IBMX. Membrane fractions from cells treated with 4 beta-PMA or 4 alpha-PMA did not differ in their contents of either basal or rAP-II-stimulated guanylate cyclase activities. We conclude that the 4 beta-PMA-mediated inhibition of testosterone production by Leydig cells stimulated with rAP-II results from an activation of a phosphodiesterase enzyme, hypothetically through an activated protein kinase C. This leads to a reduction in the cellular cGMP content through an increased metabolic removal of cGMP formed in response to rAP-II stimulation.
...
PMID:Effect of a tumour-promoting phorbol ester on atrial peptide-induced testosterone production and cyclic GMP accumulation by isolated mouse Leydig cells. 283 43

Using cultured rat vascular smooth muscle cells (VSMC), the effect of protein kinase C activation on rat atrial natriuretic peptide (rANP) receptors and its effector system was studied. Tetradecanoyl phorbol acetate (TPA) induced a time- and temperature-dependent decrease of 125I-rANP binding to VSMC. TPA and phorbol dibutyrate inhibited the binding in a dose-related manner, whereas biologically inactive beta-phorbol was ineffective. Pretreatment of VSMC with TPA resulted in a marked reduction (50-70%) of rANP binding capacity without a significant change of its binding affinity. TPA pretreatment also induced attenuation of rANP-induced cGMP generation without affecting its basal levels. These data suggest that protein kinase C may be involved in the mechanism of heterologous down-regulation of vascular ANP receptors/guanylate cyclase system.
...
PMID:Heterologous down-regulation of vascular atrial natriuretic peptide receptors by phorbol esters. 283 79

Protein kinase C catalyzes phosphorylation of purified rat brain guanylate cyclase. The phosphorylation is marked by concomitant increase in guanylate cyclase activity. TPA further enhances both phosphorylation and activity of guanylate cyclase. Data seem to provide clues to the molecular mechanism of one of the transformation-like responses mimicked by 12-O-tetradecanoylphorbol-13-acetate, i.e. the elevation of cyclic GMP. It is envisaged that protein kinase C may have a central role in the understanding of molecular events triggering carcinogenesis.
...
PMID:Protein kinase C catalyzes phosphorylation of guanylate cyclase in vitro. 285 74

Rat adrenocortical carcinoma cells possess a high density of atrial natriuretic factor (ANF) receptors which are coupled with membrane guanylate cyclase and corticosterone production. Herein we show that pretreatment of these cells with phorbol 12-myristate 13-acetate (PMA), a known activator of protein kinase C, attenuates the ANF-stimulated cyclic GMP accumulation in a dose-dependent manner. The half maximum inhibitory concentration of PMA was 10(-10) M. When these cells were incubated with PMA in the presence of 1-(5-isoquinolinyl-sulfonyl)-2-methyl piperazine, a protein kinase C inhibitor, the PMA-mediated attenuation of ANF-stimulated cyclic GMP formation is blocked. These results suggest that protein kinase C negatively regulates the ANF-receptor coupled membrane guanylate cyclase system in these cells.
...
PMID:Negative regulation of atrial natriuretic factor receptor coupled membrane guanylate cyclase by phorbol ester. Potential protein kinase C regulation of cyclic GMP signal in isolated adrenocortical carcinoma cells of rat. 289 95

alpha 2-adrenergic receptor-mediated signal transduction in rat adrenocortical carcinoma cells occurs through the opposing regulation of two second messengers, cyclic GMP and cyclic AMP, in which guanylate cyclase is coupled positively and adenylate cyclase negatively to the receptor signal. We now show that in these cells phorbol 12-myristate 13-acetate (PMA), a known activator of protein kinase C, inhibits the alpha 2-agonist (p-aminoclodine)-dependent production of cyclic GMP in a dose-dependent and time-dependent fashion. The half-maximal inhibitory concentration of PMA was 10(-10) M. A protein kinase C inhibitor, 1-(5-isoquinolinyl-sulfonyl)-2-methyl piperazine (H-7), caused the release of the PMA-dependent attenuation of p-aminoclodine-stimulated cyclic GMP formation. These results suggest that protein kinase C negatively regulates the alpha 2-receptor coupled cyclic GMP system in these cells, a feature apparently shared with the other cyclic GMP-coupled receptors such as those of muscarine, histamine, and atrial natriuretic factor.
...
PMID:Inhibition of alpha 2-adrenergic receptor-mediated cyclic GMP formation by a phorbol ester, a protein kinase C activator. 290 36

PAF elicits a rapid, concentration-dependent elevation of platelet cytosolic free calcium ([Caf]), measured by quin2. Elevation of [Caf] is transient, and the rate of reversal increases with agonist concentration. Adenylate cyclase stimulants (PGI2, PGD2) and 8-bromo cAMP; a guanylate cyclase stimulant (sodium nitroprusside) and 8-bromo cGMP; and a protein kinase C stimulant (phorbol myristate acetate) block the elevation of [Caf] induced by PAF, and accelerate its reversal. These results suggest that cAMP, cGMP and 1,2-diacylglycerol (DAG) could act as second messengers to regulate [Caf] in platelets. As PAF is known to stimulate platelet phosphoinositide hydrolysis (ergo DAG formation) but fails to elevate platelet cAMP or cGMP, it is proposed that DAG, via activation of protein kinase C, may act as an endogenous modulator of platelet [Caf]: an action that contributes to the role of DAG as a bi-directional regulator of platelet reactivity.
...
PMID:Regulation of platelet cytosolic free calcium by cyclic nucleotides and protein kinase C. 299 27

In the aortas and mesenteric arteries from spontaneous hypertensive rats and in the aortas from stress- and desoxycorticosterone-acetate-hypertensive rats, the intracellular cGMP: cAMP ratios were significantly elevated when compared to the ratios in the aortas of the respective controls. Decreases in the intracellular cAMP or cGMP levels were consistently associated with increased activity of the cyclic-nucleotide-specific low K(m) phosphodiesterase (3':5'-cAMP 5' nucleotidohydrolase, EC 3.1.4.17). Increases in intracellular cGMP levels were associated with elevated guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] activity. Furthermore, adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity was less sensitive to stimulation by the beta-adrenergic stimulant isoproterenol in both the aortas and the hearts of the hypertensive animals. These changes could provide the biochemical basis for the (a) increased vascular smooth muscle tone and peripheral resistance observed in these animals, (b) increased reactivity to norepinephrine, and (c) decreased ability of aortas from hypertensive rats to relax. The presence of these same effects in different etiologic types of hypertension indicates that this aberration in cyclic nucleotide metabolism may represent a common metabolic defect basic to the hypertensive syndrome irrespective of etiology.
...
PMID:Aberrations of cyclic nucleotide metabolism in the hearts and vessels of hypertensive rats. 415 74


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---