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PubMed1994

Cyclic GMP and regulation of cyclic nucleotide hydrolysis.

Several of the different PDE isozyme families have the ability in vitro to hydrolyze cGMP. In particular they include the CaM-dependent PDEs, the cGMP-stimulated PDEs, and the cGMP binding, cGMP-specific PDEs. Existing evidence suggests or demonstrates that in different cell types, each of these can be important determinants for the control of cGMP steady-state levels. Each of these enzymes is differentially expressed and regulated; moreover, the amount of the enzyme expressed and the mode of regulation determine to a large extent the rate of rise, maximal level, rate of fall, and duration of the cGMP signal in the cell. In addition to enzymes that function to degrade cGMP at least two also are regulated by cGMP both in vitro and in the intact cell. The cGMP-stimulated PDE has the ability to decrease cAMP levels in response to cGMP and the cGMP-inhibited PDE can increase cAMP levels in response to cGMP. We are just beginning to define how many different isozymes of PDE exist in mammalian tissues, where they are located, and how they are regulated. Selective inhibitors to each are being developed and studies designed to define structural features that determine the mechanisms of action and regulation of the PDEs have been initiated. It is expected that in the next few years more PDEs will be discovered and the functions of the new an existing ones with be more clearly defined.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

Hemodynamic effects of dibutyryl cyclic GMP in anesthetized dogs.

Dibutyryl cyclic GMP was given intravenously to anesthetized dogs with doses of 0.0625, 0.125, 0.25, 0.5 and 1.0 mg/kg, respectively. It induced decreases in blood pressure, heart rate, max LV dp/dt and total peripheral resistance with increase of stroke volume in a dose-dependent manner. Although these effects began to appear 30 sec after the administration in each dose, the duration of the effect was observed 50 sec after the administration. Effects of 1 mg/kg dibutyryl cyclic GMP on mean blood pressure and max LV dp/dt were almost equal to those of 3 micrograms/kg acetylcholine, but dibutyryl cyclic GMP was revealed to have a slower onset and longer acting effects than acetylcholine. The administration of atropine did not block the effect of dibutyryl cyclic GMP but blocked those of acetylcholine. These results indicate that dibutyryl cyclic GMP does not exert these effects through muscarinic receptors in spite of its acetylcholine-like effects.

Acetylcholine↗
PubMed1977

Modification of human DNA-dependent RNA polymerase activity by cyclic GMP.

The effect of low concentrations of cyclic GMP (guanosine 3':5'-cyclic monophosphate) on the in vitro enzymatic activities of DNA-dependent RNA polymerases isolated from human peripheral blood lymphocytes has been investigated. In agreement with earlier studies which employed isolated nuclei as the enzyme source, an increase in the activity of partially purified RNA polymerase I is observed in the presence of cyclic GMP (10(-8) to 10(-10)M). RNA polymerase II activity is inhibited by the presence of cyclic GMP at concentrations between 10(-4) and 10(-10)M. RNA polymerase III activity is stimulated in a bimodal fashion by the presence of cyclic GMP with maximal activity noted at 10(-8) to 10(-10) M and 10(-5)M. In addition, [3H]cyclic GMP binds specifically to chromatographic fractions which are known to contain RNA polymerases I, II and III. This binding to RNA polymerases II and III is apprarently less tenacious as demonstrated by dissociation studies. The observations provide additional evidence for a role for cyclic GMP in the regulation of RNA synthesis.

Cyclic AMP↗
PubMed1975

Cylic nucleotide phosphodiesterase in silkworm. Characterization of cyclic GMP phosphodiesterase.

The existence of cyclic GMP phosphodiesterase (EC 3.1.4.-) was demonstrated in silkworm larva by gel filtration of the homogenate. The cyclic GMP phosphodiesterase was separated from cyclic AMP phosphodiesterases by column chromatography on hydroxyapatite and Sephadex G-200. The enzyme has a molecular weight of approx. 260 000, and optimum pH of 8.3 and a Km value of 2 muM. The enzyme is activated by 5 mM of Mg2+ and 2 mM of Mn2+. The cyclic GMP phosphodiesterase activity was greatly inhibited by low concentrations of cyclic IMP but to a lesser extent by cyclic AMP even at a high concentration. The activity was also inhibited by caffeine and theophylline.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Phosphorylation of bovine rod photoreceptor cyclic GMP phosphodiesterase.

The cyclic GMP phosphodiesterase (PDE) of retinal rods plays a key role in phototransduction and consists of two catalytic subunits (PDE alpha and PDE beta) and two identical inhibitory subunits (PDE gamma). Here we report that PDE alpha and PDE gamma are phosphorylated by protein kinase(s) C (PKC) from brain and rod outer segments (ROS). These same two types of PKC also phosphorylate PDE alpha in trypsin-activated PDE (without PDE gamma). In contrast, cyclic-AMP-dependent protein kinase catalytic subunit phosphorylates both PDE alpha and PDE beta, but not PDE gamma. This kinase does not phosphorylate trypsin-activated PDE. The synthetic peptides AKVISNLLGPREAAV (PDE alpha 30-44) and KQRQTRQFKSKPPKK (PDE gamma 31-45) inhibited phosphorylation of PDE by PKC from ROS. These data suggest that sites (at least one for each subunit) for phosphorylation of PDE by PKC are localized in these corresponding regions of PDE alpha and PDE gamma. Isoenzyme-specific PKC antibodies against peptides unique to the alpha, beta, gamma, delta, epsilon and zeta isoforms of protein kinase C were used to show that a major form of PKC in ROS is PKC alpha. However, other minor forms were also present.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1987

A cholera toxin substrate regulates cyclic GMP content of rat pinealocytes.

The adrenergic regulation of cyclic GMP in isolated pinealocytes was investigated. In this cell, norepinephrine stimulates cyclic GMP and cyclic AMP greater than 100-fold by activating both alpha 1- and beta-adrenoceptors. beta-Adrenergic activation is a requisite event and is potentiated by alpha 1-adrenergic activation (Vanecek, J., Sugden, D., Weller, J. L., and Klein, D. C. (1985) Endocrinology 116, 2167-2173). The current study found that cholera toxin could substitute for beta-adrenergic agonists in stimulating pinealocyte cyclic GMP content, as has been found to be the case for cyclic AMP. Treatment with cholera toxin alone (1 microgram/ml for 90 min) had a small effect (2- to 4-fold increase) on cyclic GMP; addition of the alpha 1-adrenergic agonists, phenylephrine, cirazoline, or methoxamine to cholera toxin-treated cells rapidly (peak at 5 min) caused a further 30- to 300-fold increase. The alpha 1-adrenergic agonists had little effect by themselves at concentrations which potentiated the effects of cholera toxin. The potentiating effect of phenylephrine was inhibited nearly completely by an alpha 1-adrenergic antagonist, but not by either an alpha 2- or beta-adrenergic antagonist. The purified cholera toxin subunits A and B did not stimulate cyclic GMP either alone or in the presence of phenylephrine. Furthermore, the potentiating action of phenylephrine was observed following 90 min but not 20 min of cholera toxin pretreatment. these results suggest that the regulation of cyclic GMP levels in the pineal gland involves an Ns-like GTP-binding regulatory protein. This is of interest because it is the first indication that cyclic GMP is regulated by such a GTP-binding protein in nonretinal tissue. It remains to be determined whether the mechanisms involved in the transmembrane regulation of cyclic AMP and cyclic GMP in any other tissue are similar.

Animals↗
PubMed1986

Calcium induces cyclic GMP formation in Dictyostelium.

Cyclic GMP is rapidly formed a few seconds after binding of chemotactic signalling molecules to specific receptors on the cell surface of Dictyostelium amoebae. This phenomenon could be mimicked by addition of a pulse of Ca2+ to permeabilised amoebae. The concentration of Ca2+ for half-maximal response was 60 microM. Other ions (K+, Na+, Mg+ or Mn+) had no effect. A pulse of 5 microM IP3 produced a cyclic GMP response of similar magnitude but IP2 elicited no response. The data provide strong support for the hypothesis that cell surface receptor binding induces cyclic GMP formation by liberating Ca2+ from internal stores.

Journal Article↗
PubMed1980

In vivo effects of noradrenaline and noradrenergic receptor agonists and antagonists on rat cerebellar cyclic GMP levels.

Cerebellar cyclic GMP levels can be altered by neurotransmitters and their receptor agonists and antagonists. In this study, we investigated the action of noradrenaline and certain drugs affecting alpha- and beta-adrenoceptors on rat cerebellaceptor agonists such as methoxamine and phenylephrine increased cGMP levels. alpha-Adrenoceptor antagonists such as phentolamine, phenoxybenzamine and ARC 239 decreased cGMP levels, whereas yohimbine and piperoxane which are known to act as presynaptic alpha-adrenoceptor antagonists had no effect. The action of clonidine which decreased cGMP levels at low doses was probably due to the fact that this adrenoceptor agonist inhibited the release of noradrenaline from adrenergic nerve terminals, since piperoxane injected prior to clonidine antagonized the effect of clonidine on cerebellar cGMP, and since pretreatment of the animals with 6-hydroxydopamine partially antagonized the effect of clonidine. Isoproterenol, a beta-noradrenergic agonist had no effect on cerebellar cGMP levels. Propranolol, a beta-noradrenergic antagonist decreased cGMP levels. Phenoxybenzamine or propranolol injected prior to noradrenaline decreased cerebellar cGMP.

Adrenergic alpha-Agonists↗
PubMed1983

Cellular mechanism involved in the synthesis of cyclic GMP in nervous tissues.

Intracellular cyclic GMP content responds to the stimulation of muscarinic receptor in a variety of tissues. Several aspects of the cellular mechanism involved in the synthesis of cyclic GMP were investigated. 1. In cultured bovine chromaffin cells, acetylcholine as well as muscarine stimulated the 32Pi incorporation into phosphatidic acid, induced Ca2+ mobilization across the cells, and, in parallel, elevated intracellular cyclic GMP content. Phosphatidic acid added to culture medium also stimulated the efflux and influx of Ca2+ and the synthesis of cyclic GMP in bovine chromaffin cells and in neuroblastoma cells in the same fashion as acetylcholine. 2. We have succeeded in a purification of an endogenous activator for guanylate cyclase from rat brain and identified it as L-arginine. L-Arginine, but not D-arginine, activated soluble guanylate cyclase 10- to 20-fold at a low concentration (1-2 X 10(-5) M). The activation of the enzyme by L-arginine seemed to require Ca2+. Calcium accumulated in cells in response to muscarinic stimulation would activate guanylate cyclase in collaboration with L-arginine. 3. Using a specific monoclonal antibody, we demonstrated the cellular and subcellular localizations of guanylate cyclase in rat brain. An intense reaction was observed in the brain regions which were rich in muscarinic receptor. Electron microscopic examination revealed that guanylate cyclase was concentrated in the postsynaptic perikaryon and dendrites of some type of neurons indicating its involvement in neural transmission.

Acetylcholine↗
PubMed1988

Attomole sensitive radioimmunoassay for cyclic GMP.

The sensitivity of the radioimmunoassay for cyclic GMP has been improved to readily detect attomole (200-300) amounts of the nucleotide in tissue extracts. The improved sensitivity has been achieved by using a high specific radioactivity [125I] cyclic GMP 2'O-succinyl tyrosine methyl ester (2200 Ci/mmole) as labeled antigen in conjunction with acetylation of the cyclic GMP in the samples as well as by using a selected cyclic GMP antibody. The high specific [125I] cyclic GMP 2'O-succinyl tyrosine methyl ester was prepared radiochemically pure by radioiodination of cyclic GMP 2'O-succinyl tyrosine methyl ester and purification using HPLC. The new attomole sensitive cyclic GMP radioimmunoassay is simple to perform and fast and has been applied with success to determine attomole quantities of cyclic GMP in cultured smooth muscle cells and AG 1523 fibroblasts.

Animals↗
PubMed1996

Melatonin effect on the cyclic GMP system in the golden hamster retina.

Melatonin effect on retinal cyclic GMP accumulation, guanylate cyclase activity, cyclic GMP content and cyclic GMP phospho-diesterase activity was examined in the Syrian hamster retina. Melatonin increased significantly cyclic GMP accumulation at picomolar concentrations and in a time-dependent manner. The kinetic analysis of guanylate cyclase activity revealed a significant increase of both apparent Vmax and K(m), induced by 10 nM melatonin. The effect of melatonin was higher in the absence, than in the presence of the phoshodiesterase inhibitor (IBMX), suggesting an effect on cyclic GMP catabolism. Phosphodiesterase activity was significantly decreased by melatonin. The results show a dual effect of melatonin on cyclic GMP levels, i.e. by increasing the synthesis and inhibiting the degradation, both resulting in an increase of cyclic GMP levels. Taking into account the key role of cyclic GMP in visual mechanisms, the results would suggest the participation of melatonin in retinal physiology.

Animals↗
PubMedDate not supplied

Catecholamine-mediated elevation of cyclic GMP in the rat C-6 glioma cell line.

Catecholamines cause an elevation of both cyclic GMP and cyclic AMP levels in the rat C-6 glioma cell line. The response is mediated by a beta-receptor, with a Ka for stimulation of cyclic GMP of 2.6 X 10(-7)M. Maximum levels of cyclic GMP are reached by 5 min. whereas cyclic AMP levels are maximal by 10 min. Removal of calcium decreases the cyclic GMP elevation by 60%. Refractoriness to a second treatment with catecholamine develops for both responses. Catecholamine sensitivity of the cyclic GMP-generating system appears in the cells only as they start to contact and enter the stationary growth phase. In contrast to the effects of catecholamines, cholinergic agonists have no effect on either cyclic GMP or cyclic AMP levels.

Animals↗
PubMed1979

Studies on the specificity of immunohistochemical techniques for cyclic AMP and cyclic GMP.

UNLABELLED: Immunohistochemical studies employing antibodies against cyclic nucleotides indicate that cyclic AMP and cyclic GMP are localized to distinct subcellular sites. These antibodies, however, cross-react weakly with noncyclic nucleotides (eg. ATP, GTP), and therefore we investigated the speficity of the immunohistochemical technique. Slides of fetal nuclei exposed to gaseous nitrous acid demonstrated reduced immunofluorescence. The slides were then incubated with cyclic and noncyclic nucleotides, and restoration of distinct cyclic AMP and cyclic GMP staining pattern was achieved only with appropriate cyclic nucleotides. Antibodies that were used have a greater affinity for acetylated derivatives of cyclic nucleotides. By using a gas phase technique, tissue slices were acetylated and immunohistochemical staining intensity was compared with the effect of acetylation on antibody affinity for various nucleotides. Acetylation greatly increased affinity of cyclic AMP antibody for cyclic AMP but not other nucleotides, and greatly intensified cyclic AMP staining. Acetylation moderately increased affinity of cyclic GMP antibody for cyclic GMP, and moderately intensified cyclic GMP staining. CONCLUSION: Both nitrous acid and acetylation studies support the specificity of the immunohistochemical method for cyclic nucleotides.

Acetylation↗
PubMed1983

Inhibition of p-aminohippurate transport by cyclic GMP in rat kidney cortical slices.

The effect of cyclic GMP on the accumulation of p-aminohippurate (PAH) was investigated by using rat kidney cortical slices. When the slices were preincubated with cyclic GMP and thereafter incubated in the absence of the cyclic nucleotide for the assay of PAH transport, cyclic GMP inhibited PAH accumulation in the slices in a dose-dependent fashion. Pretreatment of the slices with dibutyryl cyclic GMP induced no inhibition of PAH uptake, but that with the combination of cyclic GMP and butyrate inhibited the accumulation to the same extent as did cyclic GMP. Guanosine and its monophosphate (GMP) had no effect on PAH accumulation in the slices. Inhibitory effect of cyclic GMP on PAH accumulation was not due to the changes of electrolyte content and water distribution in the slices. The slices pretreated with cyclic GMP at 0 degree C failed to decrease PAH accumulation. Cyclic GMP had no effect on organic cation (tetraethylammonium, TEA) transport in the slices. These evidence suggest that cyclic GMP may be able to modulate the rat renal transport system for PAH although this study does not explain the mechanism of inhibition of PAH transport by the cyclic nucleotide.

Aminohippuric Acids↗
PubMed1981

Epidermal cyclic GMP is increased in psoriasis lesions.

Cyclic GMP levels in epidermis of normal subjects and of psoriatic patients were measured with a highly sensitive radioimmunoassay method. Technical improvements for the assay are 2-fold: (1) skin samples were frozen in vivo before biopsy and local injection of any anesthetic was avoided to overcome ischemia effect which could lower cyclic GMP artificially; (2) epidermis was microdissected to avoid contamination of dermis and keratin layers. The results show that on a per mg tissue dry weight basis the cyclic GMP levels are about 200 fmol in the involved lesional epidermis and 70 fmol in the uninvolved or normal epidermis. Similarly increases in the cyclic GMP levels in the lesional epidermis are observed when the data are expressed either on a DNA or protein basis. The cyclic GMP level in normal epidermis from nonpsoriatic subjects is the same as that in the uninvolved epidermis of psoriasis patients.

Cyclic GMP↗
PubMed1990

Dimethylphenylpiperazinium (DMPP)-induced relaxation and elevation of cyclic GMP content in canine lower esophageal sphincter (LES).

Cyclic GMP has been proposed as an intracellular mediator of neuronally-induced relaxation in lower esophageal sphincter (LES) smooth muscle. If cyclic GMP is indeed an intracellular messenger, then agents that activate enteric neurons of the sphincter [e.g. the ganglionic nicotinic receptor agonist dimethylphenylpiperazinium (DMPP)] also should cause a relaxation that is associated with an increase in cyclic GMP content. In isolated smooth muscle strips of canine LES, DMPP produced a rapid relaxation that was accompanied by a significant (P less than 0.05) increase in cyclic GMP content with no change in cyclic AMP content. Pretreatment of tissues with either tetrodotoxin or hexamethonium antagonized both the DMPP-induced relaxation and the associated increase in cyclic GMP. The combination of phentolamine and meclofenamic acid also antagonized both the relaxation and the elevation of cyclic GMP produced by DMPP. Electrical field stimulation (EFS)-induced relaxation and elevation in cyclic GMP was unaltered by meclofenamic acid and phentolamine. In conclusion, DMPP (like neuronal electrical activation) relaxed isolated canine LES through an enteric neuronal inhibitory pathway. The presence of phentolamine and meclofenamic acid did not affect EFS-induced effects, but blocked both the relaxation and the increase in cyclic GMP produced by DMPP, suggesting a more complicated pathway for DMPP in the release of inhibitory transmitter.

Animals↗
PubMed1992

The pineal adrenergic----cyclic GMP response develops two weeks after the adrenergic----cyclic AMP response.

Pineal metabolism is regulated primarily by noradrenergic innervation. Stimulation of the adult gland with norepinephrine elevates both cyclic AMP and cyclic GMP production, through remarkably similar mechanisms requiring activation of both beta- and alpha 1-adrenergic receptors. As described here, however, the adrenergic stimulation of cyclic GMP is first detectable about 2 weeks after the cyclic AMP response can be detected. This indicates there is a profound difference in when cyclic AMP- and cyclic GMP-regulated processes can be adrenergically regulated.

Animals↗