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)

Cyclic AMP is the primary second messenger mediating odorant signal transduction in mammals. A number of studies indicate that cyclic GMP is also involved in a variety of other olfactory signal transduction processes, including adaptation, neuronal development, and long-term cellular responses in the setting of odorant stimulation. However, the mechanisms that control the production and degradation of cGMP in olfactory sensory neurons (OSNs) remain unclear. Here, we investigate these mechanisms using primary cultures of OSNs. We demonstrate that odorants increase cGMP levels in intact OSNs in vitro. Different from the rapid and transient cAMP responses to odorants, the cGMP elevation is both delayed and sustained. Inhibition of soluble guanylyl cyclase and heme oxygenase blocks these odorant-induced cGMP increases, whereas inhibition of cGMP PDEs (phosphodiesterases) increases this response. cGMP PDE activity is increased by odorant stimulation, and is sensitive to both ambient calcium and cAMP concentrations. Calcium stimulates cGMP PDE activity, whereas cAMP and protein kinase A appears to inhibit it. These data demonstrate a mechanism by which odorant stimulation may regulate cGMP levels through the modulation of cAMP and calcium level in OSNs. Such interactions between odorants and second messenger systems may be important to the integration of immediate and long-term responses in the setting odorant stimulation.
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PMID:Regulation of intracellular cyclic GMP levels in olfactory sensory neurons. 1618 24

Concepts of cAMP signalling have changed dramatically from the linear cascades of just a few years ago, with the realization that numerous cellular processes affect this motif. These influences include other signalling pathways--most significantly Ca2+, scaffolding proteins (which are themselves variously regulated) to organize the elements of the pathway, and subcellular targeting of components. An obvious implication of this organization is that global measurements of cAMP may trivialize the complexity of the cAMP signals and obscure the regulation of targets. In this presentation, current developments on the targeting and assembly of ACs (adenylate cyclases) and their delivery to selected raft or non-raft domains of the plasma membrane will be discussed, along with the susceptibility of raft-targeted ACs to very discrete modes of increases in the intracellular Ca2+ concentration. Single-cell explorations of cAMP dynamics, as measured with cyclic nucleotide-gated channels, are also described in this paper, particularly as applied to cells in which the composition of AKAP (A-kinase anchoring protein)-PKA (protein kinase A)-PDE (phosphodiesterase) assemblies is probed by RNA interference ablation of defined AKAPs.
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PMID:Compartmentalization of adenylate cyclase and cAMP signalling. 1624 8

Using combined dominant-negative and siRNA (small interfering RNA)-mediated knockdown strategies, the functional importance of specific PDE4 (phosphodiesterase-4) isoforms in modifying signalling through the beta2-AR (beta2-adrenoceptor) has been uncovered. The PDE4D5 isoform preferentially interacts with the signalling scaffold protein beta-arrestin and is thereby recruited to the beta2-AR upon agonist challenge. Delivery of an active PDE to the site of cAMP synthesis at the plasma membrane specifically attenuates the activity of a pool of PKA (protein kinase A) that is tethered to the beta2-AR via AKAP79 (A-kinase anchoring protein 79). The specific functional role of this anchored PKA is to phosphorylate the beta2-AR and allow it to switch its coupling with G(i) and thereby activation of ERK (extracellular-signal-regulated kinase). Our studies uncover a novel facet of the regulation of beta2-AR signalling by showing that beta-arrestin-recruited PDE4 provides the means of desensitizing the agonist-dependent coupling of beta2-AR with G(i) and its consequential activation of ERK.
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PMID:Beta-arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated switching of beta2-adrenoceptor signalling to activation of ERK. 1624 12

This article discusses the role of phosphodiesterase-5 (PDE-5) inhibition in the molecular biology of erectile function and dysfunction. Commercially marketed PDE-5 inhibitors are highly specific for PDE-5, and in the face of continuing cyclic GMP (cGMP) synthesis,elevate cellular cGMP. This elevation results from direct competitive inhibition of PDE-5 and from blocking the negative feedback regulation of the enzyme. Elevation of cGMP activates cGMP-dependent protein kinase, which mediates the effects of the cGMP-signaling pathway to decrease smooth muscle tone and dilate penile vascular smooth muscle. By exploiting features of PDE-5 regulatory mechanisms that modulate PDE-5 function, the inhibitors enhance their own potencies.
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PMID:Phosphodiesterase-5 inhibition: the molecular biology of erectile function and dysfunction. 1629 Oct 34

Rolipram, a selective inhibitor of cAMP-specific phosphodiesterase 4 (PDE4), has been shown to reinforce an early form of long-term potentiation (LTP) to a long-lasting LTP (late LTP). Furthermore, it was shown that the effects of rolipram-mediated reinforcement of LTP interacts with processes of synaptic tagging (Navakkode et al., 2004). Here we show in CA1 hippocampal slices from adult rats in vitro that rolipram also converted an early form of long-term depression (LTD) that normally decays within 2-3 h, to a long-lasting LTD (late LTD) if rolipram was applied during LTD-induction. Rolipram-reinforced LTD (RLTD) was NMDA receptor- and protein synthesis-dependent. Furthermore, it was dependent on the synergistic coactivation of dopaminergic D(1) and D(5) receptors. This let us speculate that RLTD resembles electrically induced, conventional CA1 late LTD, which is characterized by heterosynaptic processes and synaptic tagging. We therefore asked whether synaptic tagging occurs during RLTD. We found that early LTD in an S1 synaptic input was transformed into late LTD if early LTD was induced in a second independent S2 synaptic pathway during the inhibition of PDE by rolipram, supporting the interaction of processes of synaptic tagging during RLTD. Furthermore, application of PD 98059 (2'-amino-3'-methoxyflavone) or U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), specific inhibitors of mitogen-activated protein kinases (MAPKs), prevented RLTD, suggesting a pivotal role of MAPK activation for RLTD. This MAPK activation was triggered during RLTD by the synergistic interaction of NMDA receptor- and D(1) and D(5) receptor-mediated Rap/B-Raf pathways, but not by the Ras/Raf-1 pathway in adult hippocampal CA1 neurons, as shown by the use of the pathway-specific inhibitors manumycin (Ras/Raf-1) and lethal toxin 82 (Rap/B-Raf).
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PMID:Mitogen-activated protein kinase-mediated reinforcement of hippocampal early long-term depression by the type IV-specific phosphodiesterase inhibitor rolipram and its effect on synaptic tagging. 1629 39

The immune system depends on chemokines to recruit lymphocytes to tissues in inflammatory diseases. This study identifies PDE8 as a new target for inhibition of chemotaxis of activated lymphocytes. Chemotactic responses of unstimulated and concanavalin A-stimulated mouse splenocytes and their modulation by agents that stimulate the cAMP signaling pathway were compared. Dibutyryl cAMP inhibited migration of both cell types. In contrast, forskolin and 3-isobutyl-1-methylxanthine each inhibited migration of unstimulated splenocytes, with little effect on migration of stimulated splenocytes. Only dipyridamole alone, a PDE inhibitor capable of inhibiting PDE8, strongly inhibited migration of stimulated and unstimulated splenocytes and this inhibition was enhanced by forskolin and reversed by a PKA antagonist. Following concanavalin A stimulation, mRNA for PDE8A1 was induced. These results suggest that in employing PDE inhibitor therapy for inflammatory illnesses, inhibition of PDE8 may be required to inhibit migration of activated lymphocytes to achieve a full therapeutic effect.
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PMID:Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes. 1669 47

Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas(*)) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Galphas(*) causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Galphas(*) increases cAMP levels in the striatum. Suprisingly, however, Galphas(*) mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Galphas(*) on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Galphas(*) mice and the cPDE inhibitor rolipram also rescues PPI deficits of Galphas(*) mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Galphas(*) mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Galphas(*). We conclude that expression of Galphas(*) within forebrain neurons causes PPI deficits because of a PKA-dependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.
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PMID:Constitutive activation of Galphas within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP. 1673 44

Crosstalk between insulin and cAMP signalling pathways has a great impact on adipocyte metabolism. Whilst Protein kinase B (PKB) is a pivotal mediator of insulin action, in some cells regulation of PKB by cAMP has also been demonstrated. Here we provide evidence that, in a phosphatidyl inositol 3-kinase dependent manner, beta3-adrenergic stimulation (using CL316243) in adipocytes induces PKB phosphorylation in the absence of insulin and also potentiates insulin-induced phosphorylation of PKB. Interestingly, insulin- and CL316243-induced PKB phosphorylation was found to be inhibited by pools of cAMP controlled by PDE3B and PDE4 (mainly in the context of insulin), whereas a cAMP pool controlling protein kinase A appeared to mediate stimulation of PKB phosphorylation (mainly in the context of CL316243). Furthermore, an Epac (exchange protein directly activated by cAMP) agonist (8-pCPT-2'-O-Me-cAMP) mimicked the effect of the PDE inhibitors, giving evidence that Epac has an inhibitory effect on PKB phosphorylation in adipocytes. Further, we put the results obtained at the level of PKB in the context of possible downstream signalling components in the regulation of adipocyte metabolism. Thus, we found that overexpression of PKB induced lipogenesis in a PDE3B-dependent manner. Furthermore, overexpression or inhibition of PDE3B was associated with reduced or increased phosphorylation of the key lipogenic enzyme acetyl-CoA carboxylase (ACC), respectively. These PDE3B-dependent effects on ACC correlated with changes in lipogenesis. The Epac agonist, 8-pCPT-2'-O-Me-cAMP, mimicked the effect of PDE3B inhibition on ACC phosphorylation and lipogenesis.
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PMID:Novel mechanisms of the regulation of protein kinase B in adipocytes; implications for protein kinase A, Epac, phosphodiesterases 3 and 4. 1683 43

PI3Kgamma is a phosphoinositide 3-kinase characterized by both lipid and protein kinase activity. It is activated by G-protein-coupled receptors and is predominantly expressed in leucocytes; in addition, recent work showed its presence in the heart and its involvement in regulating cardiac functions. In this tissue, PI3Kgamma acts as a negative modulator of contractility, by decreasing cAMP concentration through a kinase-independent mechanism. Indeed, whereas PI3Kgamma-deficient mice show an abnormal cAMP elevation, cAMP levels in knock-in mouse mutants, expressing a kinase-dead PI3Kgamma, are comparable with wild-type controls. PI3Kgamma regulates cardiac cAMP homoeostasis by forming a macromolecular complex containing PDE3B (phosphodiesterase 3B). In this complex, PI3Kgamma could regulate PDE3B activity through protein kinase A, a PDE activator.
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PMID:Identification of the macromolecular complex responsible for PI3Kgamma-dependent regulation of cAMP levels. 1685 44

beta-Adrenergic signalling mediates the positive inotropic effect of catecholamines on cardiomyocytes, mainly through cAMP generation and subsequent activation of PKA (protein kinase A). Given the large diversity of PKA targets within cardiac cells, a precisely regulated and confined activity of such signalling pathways is essential for the specificity of response. PDEs (phosphodiesterases) constitute the only cAMP-degrading mechanism and are expressed in the cardiomyocyte in at least 5 family variants. Each PDE family is characterized by unique functional properties and contributes to a cAMP-degrading system enabling the modulation of PKA activity in a stimulus-dependent fashion.
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PMID:A complex phosphodiesterase system controls beta-adrenoceptor signalling in cardiomyocytes. 1685 46


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