Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic effects of insulin are initiated by the binding of insulin to the extracellular domain of the insulin receptor within the plasma membrane of muscle and adipose and liver cells. The subsequent activation of the intracellular tyrosine protein kinase activity of the receptor leads to autophosphorylation of the receptor as well as phosphorylation of a number of intracellular proteins. This gives rise to the activation of Ras and phosphatidylinositol 3-kinase and hence to the activation of a number of serine/threanine protein kinases. Many of these kinases appear to be arranged in cascades, including a cascade that results in the activation of mitogen-activated protein kinase and another that may result in the activation of protein kinase B, leading to the inhibition of glycogen synthase kinase-3 and the activation of the 70 kiloDalton ribosomal S6 protein kinase (p70 S6 kinase). We have explored the role of these early events in the the stimulation of glycogen, fatty acid, and protein synthesis by insulin in rat epididymal fat cells. Comparisons have been made between the metabolic effects of insulin and those of epidermal growth factor, since these 2 agents have contrasting effects on p70 S6 kinase and mitogen-activated protein kinase. The effects of wortmannin (which inhibits phosphatidylinositol 3-kinase), and rapamycin (which blocks the activation of p70 S6 kinase) have also been studied. These and other studies indicate that the mitogen-activated protein kinase cascade is probably not important in the acute metabolic effects of insulin, but may have a role in the regulation of gene transcription and hence the more long-term effects of insulin. The short-term metabolic effects of insulin appear to involve at least 3 distinct signaling pathways: (1) those leading to increases in glucose transport and the activation of glycogen synthase, acetyl-CoA carboxylase, eukaryotic initiation factor-2B, and phosphodiesterase, which may involve phosphatidylinositol 3-kinase and protein kinase B; (2) those leading to some of the effects of insulin on protein synthesis (formation of eukaryotic initiation factor-4F complex, S6 phosphorylation, and activation of eukaryotic elongation factor-2), which may involve phosphatidylinositol 3-kinase and p70 S6 kinase; and finally, (3) that leading to the activation of pyruvate dehydrogenase, which is unique in apparently not requiring activation of phosphatidylinositol 3-kinase.
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PMID:Multiple signaling pathways involved in the metabolic effects of insulin. 929 55

1. An inward current (I[in]) was produced by gamma-aminobutyric acid (GABA) and muscimol, but not by baclofen, in an identifiable giant neuron type, v-LCDN (ventral-left cerebral distinct neuron), of an African giant snail (Achatina fulica Ferussac) under voltage clamp. 2. The pharmacological features of the excitatory GABA receptors in this Achatina neuron type, termed the Achatina muscimol II type GABA receptors, were mainly comparable to those of the mammalian GABA(C) receptors. 3. It was demonstrated in the present study that the following inhibitors for intracellular signal transduction systems showed no significant effect on the I(in) produced by GABA in this Achatina neuron type: H-7 [1-(5-isoquinolinyl sulfonyl)-2-methylpiperazine], an inhibitor of cyclic AMP-dependent protein kinase (PKA), cyclic GMP-dependent protein kinase (PKG) and protein kinase C (PKC); H-8 (N-[2-(methylamino)-ethyl]-5-isoquinolinesulfonamide), a PKA and PKG inhibitor; H-9 [N-(2-aminoethyl)-5-isoquinolinesulfonamide], a PKA inhibitor; staurosporine ((9alpha,10beta,11beta,13alpha)-(+)-2,3,10,11,12 ,13-hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-d iindolo[1,2,3-gh: 3',2',1'-1m]pyrrolo[3,4-j] [1,7]benzodiazonin-1-one), a PKA and PKC inhibitor; KT5823 ((8R,9S, 11S)-9-methoxy-9-methoxycarbonyl-2N,8-dimethyl-2,3,9,10-tetrahydro-8,11- epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[c,d,e]- trinden-1-one), a PKG inhibitor; W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide], a calmodulin inhibitor; ML-9 [1-(5-chloronaphthalene-1-sulfonyl-1H-hexahydro-1,4-diazepine hydrochloride], a myosin light-chain kinase inhibitor; genistein [5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one], a tyrosine protein kinase inhibitor; IBMX (3-isobutyl-1-methylxanthine), a cyclic nucleotide phosphodiesterase (PDE) inhibitor; fluphenazine nitrogen-mustard (2-chloroethyl)-4[3-(2-trifluoromethyl-10-phenothiazinyl)-propyl]p iperazine dihydrochloride), a calmodulin-dependent PDE inhibitor; calyculin A, a type 1 protein phosphatase inhibitor; and okadaic acid (9,10-deepithio-9,10-didehydroacanthifolicin), a type 1, 2A and 2B protein phosphatase inhibitor. 4. With these results, it was proposed that the excitatory Achatina muscimol II type GABA receptors in v-LCDN are not metabotropic but ionotropic.
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PMID:Effects of inhibitors for intracellular signal transduction systems on the inward current produced by GABA in a snail neuron. 950 77

In a previous paper we presented evidence for a negative regulation of adenylyl cyclase activity by tyrosine protein kinase(s) in the human leukemic T cell line Jurkat. In order to examine this point in non malignant cells, we conducted the present study in human peripheral blood mononuclear cells (PBMC). In these cells, staurosporine, a broad spectrum protein kinase inhibitor, enhanced not only the receptor-mediated, induced by prostaglandin E2 (PGE2), but also the direct (forskolin-induced) stimulation of adenylyl cyclase activity. Herbimycin A, a specific protein tyrosine kinase inhibitor, reproduced only in part the effect of staurosporine, whereas bisindolylmaleimide, the most specific protein kinase C (PKC) inhibitor known at present time, was ineffective. All these observations were made both in the absence and presence of isobutylmethylxanthine, a phosphodiesterase inhibitor, indicating that the effects of staurosporine and herbimycin A on cAMP accumulation were not due to phosphodiesterase inhibition. The calcium ionophore A 23187 also enhanced the PGE2-induced cAMP accumulation, and this effect was not additive to that of staurosporine, but additive to that of herbimycin A. These results confirm and extend those obtained in Jurkat cells. Taken together, they indicate that in human PBMC the adenylyl cyclase activity is negatively regulated by tyrosine kinase(s) and not by PKC, and positively regulated by Ca2+. They also suggest that the major enhancement by staurosporine of the PGE2-induced cAMP accumulation, although chiefly mediated by protein tyrosine kinase inhibition, also depends on another, presently undetermined, effect of the drug simulating that of Ca2+.
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PMID:Regulation of adenylyl cyclase activity in human peripheral blood mononuclear cells: effects of protein kinase inhibitors and of a calcium ionophore. 981 89

The effects on acetylcholine-induced membrane currents (ACh currents), produced by agents known to modify the activity of intracellular messengers, were studied in the neurons of the guinea-pig ileum submucous plexus (SMP) using a whole-cell patch clamp recording method. The ACh currents were not affected by forskolin, the adenylate cyclase activator, regardless of whether or not ATP and GTP were present in the intracellular solution, and by phorbol 12-myristate 13-acetate, the protein kinase C activator. The ACh currents were strongly suppressed by thapsigargin, the microsomal calcium ATPase inhibitor, and genistein, the tyrosine protein kinase inhibitor. They were also suppressed by 3-isobutyl-1-methylxanthine, the cyclic-AMP phosphodiesterase inhibitor, regardless of the presence of forskolin in the extracellular solution and ATP and GTP in the intracellular solution. In addition, the currents were suppressed by activation of P2 purinoceptors with ATP, which could not be explained by a direct effect of ATP on nicotinic acetylcholine receptors (nAChRs). Reactive blue 2, the P2y purinoceptor antagonist, did not abolish inhibition of the ACh current by ATP. Alpha,beta-Imido-ATP and adenosine caused no membrane current responses and did not influence the ACh currents. These results suggest that the activity of the nAChRs in the SMP neurons is strongly suppressed by raised intracellular Ca2+ level, without involvement of protein kinases A and C, and may involve the participation of tyrosine kinase. The activity of nAChRs is also influenced by the activity of P2 purinoceptors; the mechanisms responsible for this influence are not yet clear. So, the activity of the SMP neuronal nAChRs is relatively independent on the intracellular signaling known to influence many other groups of transmitter-gated receptors of neuronal membrane.
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PMID:Modulation of nicotinic acetylcholine receptor activity in submucous neurons by intracellular messengers. 993 65

This study was designed to investigate the dependency of the red blood cell deformability upon activation of extra- and intracellular signaling pathways. Exposures of red blood cells (RBCs) to catecholamines and to insulin led to positive change in the RBC deformability. When forskolin, a stimulator of adenylyl cyclase (AC), was added to RBC suspension, the RBC deformability was increased. Somewhat more significant deformability rise appeared after RBC incubation with dB-AMP. The inhibitors of phosphodiesterase (PDE) activity increased red cell deformability. These results revealed a considerable role of the AC-cAMP signaling system in the regulation of red blood cell deformability. The rise of the red blood cell Ca(2+) influx, stimulated by mechanical loading or A23187 was accompanied by a marked lowering of RBC deformability. At the same time blocking of Ca(2+) entry into RBC by verapamil or Ca(2+) chelating by EGTA led to significant deformability rise. The comparison of the effect of the different protein kinases on the red blood cell deformability showed that it was altered more considerable under PKA activation by forskolin or dB-cAMP than by other protein kinases. There was a lesser but quite statistically significant effect of tyrosine protein kinase (TPK) on RBC microrheology. Whereas the microrheological effect of PKC was not so considerable. The problem of the short-term regulation of red blood cell microrheology is examined. The latter includes: the modes of activation of extra- and intracellular molecular signaling pathways, ligand - receptor interaction, second messengers, membrane protein phosphorylation. On the whole the total data clearly show that the red cell deformability changes are connected with activation of different extra - and intracellular signaling pathways. It seems reasonable to suppose that red blood cell deformability changes were mainly associated with activation of the AC-cAMP-PKA pathway, and with decrease of Ca(2+) entry into cells.
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PMID:Role molecular signaling pathways in changes of red blood cell deformability. 2295 24

Pulmonary arterial hypertension is a progressive and debilitating disorder with an associated high morbidity and mortality rate. Significant advances in our understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary hypertension have occurred over the past several decades. This has allowed the development of new therapeutic options in this disease. Today, our selection of therapeutic modalities is broader, including calcium channel blockers, prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators, but the disease remains fatal. This underscores the need for a continued search for novel therapies. Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include rho-kinase inhibitors, long-acting nonprostanoid prostacyclin receptor agonists, tyrosine protein kinase inhibitors, endothelial nitric oxide synthase couplers, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.
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PMID:Existing drugs and agents under investigation for pulmonary arterial hypertension. 2509 1

Pulmonary arterial hypertension (PAH) is a vascular disorder associated with high morbidity and mortality rate and is characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in right ventricular failure and death. Over the past few decades, significant advances in the understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary arterial hypertension have occured. This has led to the development of disease specific treatment including prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators. These therapies significantly improve exercise capacity, quality of life, pulmonary hemodynamics, but none of the current treatments are actually curative and long-term prognosis remains poor. Thus, there is a clear need to develop new therapies. Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include tyrosine protein kinase inhibitors, rho-kinase inhibitors, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.
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PMID:Pulmonary arterial hypertension specific therapy: The old and the new. 3241 72