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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Phosphodiesterases (PDEs) are critically implicated in the regulation of mesangial cell function, but profile of functional PDEs in mesangial cells is still unclear. In this study, we investigated roles of individual PDEs in the regulation of mesangial cell behavior by the cAMP pathway. 2. Reporter mesangial cells that express secreted alkaline phosphatase (SEAP) under the control of the cAMP response element (CRE) were exposed to selective PDE inhibitors in the presence or absence of cAMP, and activity of CRE, expression of CRE-regulated protein, mitogenesis and cell survival were examined. 3. Exposure of reporter cells to cAMP-elevating agents resulted in time- and concentration-dependent activation of CRE. Treatment of the cells with any PDE inhibitors alone did not induce CRE activation. Under stimulation with 8-bromo-cAMP or 8-bromo-cGMP, however, inhibitors of PDE2, PDE3, PDE4 and PDE5 enhanced activation of CRE. Inhibition of PDE1 or PDE6 did not affect the CRE activation. 4. Among different combinations tested, only inhibitors of PDE3 and PDE4 cooperatively increased the level of intracellular cAMP, activity of protein kinase A, activation of CRE, and CRE-regulated protein, connexin43. 5. Concomitant inhibition of PDE3 and PDE4 attenuated mitogen-induced activation of extracellular signal-regulated kinases and cell proliferation. Under serum deprivation, combinational inhibition of PDE3 and PDE4 exclusively caused activation of caspase-3 and apoptosis. 6. The present data elucidated that PDE3 and PDE4 play critical roles in the regulation of mesangial cell function. PDE3 and PDE4 were identified as the novel, antiapoptotic machinery that supports survival of mesangial cells.
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PMID:Profiling of functional phosphodiesterase in mesangial cells using a CRE-SEAP-based reporting system. 1675 94

Inotropic agents are indispensable for the improvement of cardiac contractile dysfunction in acute or decompensated heart failure. Clinically available agents, including sympathomimetic amines (dopamine, dobutamine, noradrenaline) and selective phosphodiesterase-3 inhibitors (amrinone, milrinone, olprinone and enoximone) act via cAMP/protein kinase A (PKA)-mediated facilitation of intracellular Ca2+ mobilisation. Phosphodiesterase-3 inhibitors also have a vasodilatory action, which plays a role in improving haemodynamic parameters in certain patients, and are termed inodilators. The available inotropic agents suffer from risks of Ca2+ overload leading to arrhythmias, myocardial cell injury and ultimately, cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and cellular metabolism. Furthermore, they lose their effectiveness under pathophysiological conditions, such as acidosis, stunned myocardium and heart failure. Pimobendan and levosimendan (that act by a combination of an increase in Ca2+ sensitivity and phosphodiesterase-3 inhibition) appear to be more beneficial among existing agents. Novel Ca2+ sensitisers that are under basic research warrant clinical trials to replace available inotropic agents.
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PMID:Acute heart failure: inotropic agents and their clinical uses. 1705 76

Phosphodiesterase-5 (PDE5) inhibitors (sildenafil, vardenafil, or tadalafil) or phosphorylation by cyclic nucleotide-dependent protein kinase causes an apparent conformational change in PDE5, as indicated by a shift in migration on non-denaturing PAGE gels and an altered pattern of tryptic digestion. Combination of cGMP and a PDE5 inhibitor or phosphorylation does not cause a further gel shift or change in tryptic digest. Phosphorylation of PDE5 is stimulated by inhibitors, and combination of cGMP and inhibitor does not cause further phosphorylation. Dephosphorylation of PDE5 by either purified phosphoprotein phosphatase-1 or -2A catalytic subunit or by a crude phosphatase mixture is not affected by cGMP or inhibitors, suggesting that phosphorylation itself maintains conformational exposure of the phosphorylation site. The combined results imply that cGMP binding to the catalytic site initiates negative feedback control of many cellular cGMP signaling pathways by directly stimulating phosphorylation and activation of PDE5; by exploiting this molecular mechanism, PDE5 inhibitors stimulate their own potencies.
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PMID:Phosphorylation of phosphodiesterase-5 is promoted by a conformational change induced by sildenafil, vardenafil, or tadalafil. 1712 29

Phosphodiesterase 4 (PDE4) inhibitors stimulate osteoclast formation by increasing the TRANCE/OPG mRNA ratio via cAMP-mediated pathways in a manner similar to parathyroid hormone (PTH) in osteoblasts. We investigated the role of cyclooxygenase-2 (COX-2) in osteoclast formation induced by the PDE4 inhibitor rolipram. Rolipram induced COX-2 expression in mRNA and protein levels, followed by increased prostaglandin E(2) production in osteoblasts. PKA, ERK, and p38 MAPK pathways regulate COX-2 mRNA expression induced by rolipram, in which PKA is a central regulator of the ERK and p38 MAPK pathways. A COX-2 inhibitor reversed the up-regulation of the TRANCE/OPG mRNA ratio induced by rolipram in osteoblasts, resulting in decreased osteoclast formation. These data suggest that COX-2 mediates rolipram induced osteoclast formation by regulating the TRANCE/OPG mRNA ratio in osteoblasts. Furthermore, the effects of the PDE4 inhibitor on osteoblasts were very similar to those of PTH, indicating that the PDE4 inhibitor largely shares the biological actions of PTH in osteoblasts.
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PMID:Phosphodiesterase 4 inhibitor regulates the TRANCE/OPG ratio via COX-2 expression in a manner similar to PTH in osteoblasts. 1722 89

Phosphodiesterase (PDE) inhibitors are potent cardiotonic agents used for parenteral inotropic support in heart failure. Contractile effects of these agents are mediated through cAMP-protein kinase A-induced stimulation of I (Ca2+) which ultimately results in increased Ca(2+)-induced sarcoplasmic reticulum Ca(2+) release. A number of additional effects such as increases in sarcoplasmic reticulum Ca(2+) stores, stimulation of reverse mode Na(+)-Ca(2+) exchange, direct or cAMP-mediated effects on sarcoplasmic reticulum ryanodine receptor, stimulation of the voltage-sensitive sarcoplasmic reticulum Ca(2+) release mechanism, as well as A(1) adenosine receptor blockade could contribute to positive inotropic responses to PDE inhibitors. Moreover, some PDE inhibitors exhibit Ca(2+) sensitizer properties as they could increase the affinity of troponin C Ca(2+)-binding sites as well as reduce Ca(2+) threshold for thin myofilament sliding and facilitate cross-bridge cycling. Inotropic responses to PDE inhibitors are significantly reduced in cardiac disease, an effect largely attributed to downregulation of cAMP-mediated signalling due to sustained sympathetic activation. Four PDE isoenzymes (PDE1, PDE2, PDE3 and PDE4) are present in myocardial tissue of various mammalian species, of which PDE3 and PDE4 are particularly involved in regulation of cardiac myocyte contraction. PDE cAMP-hydrolysing activity is preserved in compensated cardiac hypertrophy but significantly reduced in animal models of heart failure. However, clinical studies have not revealed any changes in distribution profile as well as kinetic and regulatory properties of myocardial PDEs in failing human hearts. A reduction of PDE inhibitors-induced contractile responses in heart failure has therefore been ascribed to reduced cAMP synthesis due to uncoupling of adenylyl cyclase from beta-adrenoreceptor. In cardiac myocytes, PDEs are targeted to distinct subcellular compartments by scaffolding proteins such as myomegalin, mAKAP and beta-arrestins. Over subcellular microdomains, cAMP hydrolysis by PDE3 and PDE4 allows to control the activity of local pools of protein kinase A and therefore the extent of protein kinase A-mediated phosphorylation of cellular proteins.
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PMID:Myocardial phosphodiesterases and regulation of cardiac contractility in health and cardiac disease. 1750 72

We demonstrate here the regulatory role of cAMP in cell cycle of Candida albicans. cAMP was found to be a positive signal for growth and morphogenesis. Phosphodiesterase inhibitor aminophylline exhibited significant effects, i.e., increased growth, as well as induced morphogenesis. Atropine and trifluoperazine negatively regulated (inhibited) growth and did not induce morphogenesis. These changes were attributed to increase in cAMP levels and protein kinase A (PKA) activity in presence of aminophylline, while reduction was observed in atropine and trifluoperazine (TFP) grown cells. Alteration in cAMP signaling pathway affected the cell cycle progression in Candida albicans. Increased cAMP levels in aminophylline grown cells reduced the duration of cell cycle by inciting the cell cycle-specific expression of G1 cyclins (CLN1 and CLN2). However atropine and trifluoperazine delayed the expression of G1 cyclins and hence prolonged the cell cycle. Implication of cAMP signaling pathway in both the cell cycle and morphogenesis further opened the channels to explore the potential of this pathway to serve as a target for development of new antifungal drugs.
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PMID:cAMP regulates vegetative growth and cell cycle in Candida albicans. 1755 92

Recent experimental evidence suggests that arterial insufficiency precedes the structural and functional changes in corpora cavernosa (CC) leading to organic erectile dysfunction (ED). The present review gives an overview of the physiological factors involved in the regulation of penile vasculature. Sympathetic nerves maintain flaccidity and tonically released noradrenaline induces vasoconstriction of both arteries and veins through alpha(1)- and alpha(2)-postsynaptic receptors and downregulates its own release and that of nitric oxide (NO) through alpha(2)-presynaptic receptors. The sympathetic cotransmitter neuropeptide Y (NPY) modulates noradrenergic vasoconstriction in penile small arteries by both enhancing and depressing noradrenaline contractions through Y(1)- and Y(2)-postsynaptic and a NO-independent atypical endothelial receptor, respectively. Activation of alpha(1)-adrenoceptors involves both Ca(2+) influx through L-type and receptor-operated Ca(2+) channels (ROC) and Ca(2+) sensitization mechanisms mediated by protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase (RhoK). In addition, RhoK can regulate Ca(2+) entry in penile arteries upon receptor stimulation. Vasodilatation of penile arteries and large veins during erection is mediated by neurally released NO. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining penile arteries activates endothelial NO production through Akt phosphorylation of endothelial NO synthase (eNOS). NO stimulates guanylate cyclase and increased cyclic guanin 3'-monophosphate (cGMP) levels in turn activate protein kinase G (PKG), which enhances K(+) efflux through Ca(2+)-activated (K(Ca)) and voltage-dependent Ca(2+) (K(v)) channels in penile arteries and veins, respectively. PKG-mediated decrease in Ca(2+) sensitivity and its regulation by RhoK remains to be clarified in penile vasculature. Phosphodiesterase type 5 (PDE5) inhibitors are potent vasodilators of penile resistance arteries and increase the content and effects of basally released endothelial NO. Endothelium-dependent relaxations of penile small arteries also include an endothelium-derived hyperpolarizing factor (EDHF)-type response, which is impaired in diabetes and hypertension-associated ED. Locally produced contractile and relaxant prostanoids regulate penile venous and arterial tone, respectively. The latter activates prostaglandin I (IP) and prostaglandin E (EP) receptors coupled to adenylate cyclase and to the increase of cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates K(+) efflux through ATP-sensitive K(+) (K(ATP)) channels. There is a crosstalk between the cGMP and cAMP signaling pathways in penile small arteries. Relevant issues such as the mechanisms underlying the excitation-secretion coupling of the endothelial cells, as well as those involved in cell proliferation and vascular remodeling of the penile vasculature remain to be elucidated. In addition, only few studies have investigated the changes in structure and function of penile arteries in cardiovascular risk situations leading to ED.
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PMID:Physiological regulation of penile arteries and veins. 1763 89

Cardiovascular disease is the leading cause of morbidity and mortality in industrial societies, with myocardial infarction as the primary assassin. Pharmacologic agents, including the myocardial cell membrane receptor agonists adenosine, bradykinin/angiotensin-converting enzyme inhibitors, opioids and erythropoietin or the mixed cell membrane and intracellular agonists, glucose insulin potassium, and volatile anesthetics, either clinically or experimentally reduce the extent of myocardial injury when administered just prior to reperfusion. Agents that specifically target proteins, transcription factors or ion channels, including PKC agonists/antagonists, PPAR, Phosphodiesterase-5 inhibitors, 3-Hydroxy-3-methyl glutaryl coenzyme A reductase and the ATP-dependent potassium channel are also promising. However, no agent has been specifically approved to reduce reperfusion injury clinically. In this review, we will discuss the advantages and limitations of agents to combat reperfusion injury, their market development status and findings reported in both clinical and preclinical studies. The molecular pathways activated by these agents that preserve myocardium from reperfusion injury, which appear to commonly involve glycogen synthase kinase 3beta and mitochondrial permeability transition pore inhibition, are also described.
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PMID:Pharmacologic therapeutics for cardiac reperfusion injury. 1787 67

Phosphodiesterase type 5A (PDE5A) selectively hydrolyzes cyclic GMP. Inhibitors of PDE5A such as sildenafil are widely used to treat erectile dysfunction, but growing evidence supports important roles for the enzyme in both the vasculature and heart. In disorders such as cardiac failure, PDE5A upregulation may contribute to a decline in cGMP and protein kinase G signaling, exacerbating dysfunction. PDE5A plays an important role in the pulmonary vasculature where its inhibition benefits patients with pulmonary hypertension. In the heart, PDE5A signaling appears compartmentalized, and its inhibition is cardioprotective against ischemia-reperfusion and antracycline toxicity, blunts acute adrenergic contractile stimulation, and can suppress chronic hypertrophy and dysfunction attributable to pressure-overload. In this review, we discuss the molecular biology, pharmacology, and physiology of PDE5A, mechanisms of vascular and cardiac regulation, and recent evidence supporting the utility of selective PDE5A inhibition for the treatment of cardiovascular disorders.
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PMID:Phosphodiesterase type 5: expanding roles in cardiovascular regulation. 1804 25

Myocyte apoptosis plays an important role in myocardial infarction and cAMP is crucial in the regulation of myocyte apoptosis. Phosphodiesterase-4 (PDE4) inhibitor blocks the hydrolysis of cAMP via inhibition of PDE4 and is attractive candidate for novel anti-inflammatory drugs. However, its function in cardiovascular diseases and cardiomyocyte apoptosis is unclear. Therefore, we investigated whether roflumilast, a PDE4 inhibitor, exerts protective effect against NO-induced apoptosis in both of H9c2 cells and neonatal rat cardiomyocytes (NRCMs), focusing on cAMP downstream molecules such as protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). According to our data, intracellular cAMP was increased by roflumilast treatment in H9c2 cells and NRCMs. Roflumilast inhibited SNP-induced apoptosis and this effect was reversed by PKA specific inhibitor H-89 and KT-5720. In addition, PKA specific activator N(6)-benzoyladenosine 3',5-cyclic monophosphate (N(6)Bz-cAMP) mimicked the effects of roflumilast. CREB phosphorylation by roflumilast was also inhibited by H-89, indicating that roflumilast protects SNP-induced apoptosis via PKA-dependent pathway. Roflumilast increased Epac1/GTP-Rap1 and the protective effect was abolished by Epac1 siRNA transfection, demonstrating that Epac signaling was also involved in this protective response. In support, Epac specific activator 8-(4-chlrorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8CPT-2Me-cAMP) protected SNP-induced apoptosis. PI3K/Akt inhibitor LY294002 blocked roflumilast-induced Akt phosphorylation and protective effect. Furthermore, inhibition of Epac1 with siRNA had no effect on roflumilast-induced CREB phosphorylation, whereas inhibited Akt phosphorylation, implicating that Akt phosphorylation was regulated by Epac pathway. In addition, it was also observed that rolipram and cilomilast exert similar effects as roflumilast. In summary, our data indicate that roflumilast protects NO-induced apoptosis via both cAMP-PKA/CREB and Epac/Akt-dependent pathway. Our study suggests a possibility of PDE4 inhibitor roflumilast as a potential therapeutic agent against myocardial ischemia/reperfusion (I/R) injury.
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PMID:PDE4 inhibitor, roflumilast protects cardiomyocytes against NO-induced apoptosis via activation of PKA and Epac dual pathways. 1827 8


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