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

We previously reported that in mesenteric arteries from streptozotocin (STZ)-induced diabetic rats that 1) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired, possibly due to a reduced action of cAMP via increased phosphodiesterase 3 (PDE3) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283-H291, 2003) and that 2) PKA activity is decreased (Matsumoto T, Wakabayashi K, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 287: H1064-H1071, 2004). Here we investigated whether chronic treatment with cilostazol, a PDE3 inhibitor, improves EDHF-type relaxation in mesenteric arteries isolated from STZ rats. We found that in such arteries 1) cilostazol treatment (2 wk) improved ACh-, A-23187-, and cyclopiazonic acid-induced EDHF-type relaxations; 2) the ACh-induced cAMP accumulation was transient and sustained in arteries from cilostazol-treated STZ rats; 3) the EDHF-type relaxation was significantly decreased by a PKA inhibitor in the cilostazol-treated group, but not in the cilostazol-untreated group; 4) cilostazol treatment improved both the relaxations induced by cAMP analogs and the PKA activity level; and 5) PKA catalytic subunit (Cat-alpha) protein was significantly decreased, but the regulatory subunit RII-beta was increased (and the latter effect was significantly decreased by cilostazol treatment). These results strongly suggest that cilostazol improves EDHF-type relaxations in STZ rats via an increase in cAMP and PKA signaling.
...
PMID:Cilostazol improves endothelium-derived hyperpolarizing factor-type relaxation in mesenteric arteries from diabetic rats. 1590 66

Ca2+-regulated exocytosis is enhanced by an autocrine mechanism via the PGE2-cAMP pathway in antral mucous cells of guinea-pigs. The inhibition of the PGE2-cAMP pathway by H-89 (an inhibitor of protein kinase A, PKA) or aspirin (ASA, an inhibitor of cyclo-oxygenase, COX) decreased the frequency of ACh-stimulated exocytotic events by 60%. Indomethacin (IDM, an inhibitor of COX), however, decreased the frequency of ACh-stimulated exocytotic events only by 30%. Moreover, IDM increased the frequency of ACh-stimulated exocytotic events by 50% in H-89-treated or ASA-treated cells. IDM inhibits the synthesis of Prostaglandin (PGG/H) and (15R)-15-hydroxy-5,8,11 cis-13-trans-eicosatetraenoic acid (15R-HPETE), while ASA inhibits only the synthesis of PGG/H. Thus, IDM may accumulate arachidonic acid (AA). AACOCF3 or N-(p-amylcinnamoyl) anthranilic acid (ACA; both inhibitors of phospholipase A2, PLA2), which inhibits AA synthesis, decreased the frequency of ACh-stimulated exocytotic events by 60%. IDM, however, did not increase the frequency in AACOCF3-treated cells. AA increased the frequency of ACh-stimulated exocytotic events in AACOCF3- or ASA-treated cells, similar to IDM in ASA- and H-89-treated cells. Moreover, in the presence of AA, IDM did not increase the frequency of ACh-stimulated exocytotic events in ASA-treated cells. The PGE2 release from antral mucosa indicates that inhibition of PLA2 by ACA inhibits the AA accumulation in unstimulated and ACh-stimulated antral mucosa. The dose-response study of AA and IDM demonstrated that the concentration of intracellular AA accumulated by IDM is less than 100 nm. In conclusion, IDM modulates the ACh-stimulated exocytosis via AA accumulation in antral mucous cells.
...
PMID:Enhancement of Ca2+-regulated exocytosis by indomethacin in guinea-pig antral mucous cells: arachidonic acid accumulation. 1626 97

At the rat motor endplate, pre-synaptic facilitatory adenosine A2A and muscarinic M1 receptors are mutually exclusive. We investigated whether these receptors share a common intracellular signalling pathway. Suppression of McN-A-343-induced M1 facilitation of [3H]ACh release was partially recovered when CGS21680C (an A2A agonist) was combined with the cyclic AMP antagonist Rp-cAMPS. Forskolin, rolipram and 8-bromo-cyclic AMP mimicked CGS21680C blockade of M1 facilitation. Both Rp-cAMPs and nifedipine reduced augmentation of [3H]ACh release by McN-A-343 and CGS21680C. Activation of M1 and A2A receptors enhanced Ca2+ recruitment through nifedipine-sensitive channels. Nifedipine inhibition revealed by McN-A-343 was prevented by chelerythrine (a PKC inhibitor) and Rp-cAMPS, suggesting that Ca(v)1 (L-type) channels phosphorylation by PKA and PKC is required. Rp-cAMPS inhibited [3H]ACh release in the presence of phorbol 12-myristate 13-acetate, but PKC inhibition by chelerythrine had no effect on release in the presence of 8-bromo-cyclic AMP. This suggests that the involvement of PKA may be secondary to M1-induced PKC activation. In conclusion, competition of M1 and A2A receptors to facilitate ACh release from motoneurons may occur by signal convergence to a common pathway involving PKA activation and Ca2+ influx through Ca(v)1 (L-type) channels.
...
PMID:Protein kinase A and Ca(v)1 (L-Type) channels are common targets to facilitatory adenosine A2A and muscarinic M1 receptors on rat motoneurons. 1630 41

In smooth muscle of the gut, G(q)-coupled receptor agonists activate preferentially PLC-beta1 to stimulate phosphoinositide (PI) hydrolysis and inositol 1,4,5-trisphosphate (IP(3)) generation and induce IP(3)-dependent Ca(2+) release. Inhibition of Ca(2+) mobilization by cAMP- (PKA) and cGMP-dependent (PKG) protein kinases reflects inhibition of PI hydrolysis by both kinases and PKG-specific inhibitory phosphorylation of IP(3) receptor type I. The mechanism of inhibition of PLC-beta1-dependent PI hydrolysis has not been established. Neither G(q) nor PLC-beta1 was directly phosphorylated by PKA or PKG in gastric smooth muscle cells. However, both kinases 1) phosphorylated regulator of G protein signaling 4 (RGS4) and induced its translocation from cytosol to plasma membrane, 2) enhanced ACh-stimulated association of RGS4 and Galpha(q).GTP and intrinsic Galpha(q).GTPase activity, and 3) inhibited ACh-stimulated PI hydrolysis. RGS4 phosphorylation and inhibition of PI hydrolysis were blocked by selective PKA and PKG inhibitors. Expression of RGS4(S52A), which lacks a PKA/PKG phosphorylation site, blocked the increase in GTPase activity and the decrease in PI hydrolysis induced by PKA and PKG. Blockade of PKA-dependent effects was only partial. Selective phosphorylation of G protein-coupled receptor kinase 2 (GRK2), which contains a RGS domain, by PKA augmented ACh-stimulated GRK2:Galpha(q).GTP association; both effects were blocked in cells expressing GRK2(S685A), which lacks a PKA phosphorylation site. Inhibition of PI hydrolysis induced by PKA was partly blocked in cells expressing GRK2(S685A) and completely blocked in cells coexpressing GRK2(S685A) and RGS4(S52A) or Galpha(q)(G188S), a Galpha(q) mutant that binds GRK2 but not RGS4. The results demonstrate that inhibition of PLC-beta1-dependent PI hydrolysis by PKA is mediated via stimulatory phosphorylation of RGS4 and GRK2, leading to rapid inactivation of Galpha(q).GTP. PKG acts only via phosphorylation of RGS4.
...
PMID:Inhibition of Galphaq-dependent PLC-beta1 activity by PKG and PKA is mediated by phosphorylation of RGS4 and GRK2. 1688 98

We previously reported that vascular endothelial growth factor (VEGF) increases vascular permeability through the synthesis of endothelial platelet-activating factor (PAF), while others reported the contribution of nitric oxide (NO). Herein, we addressed the contribution of VEGF receptors and the role played by PAF and NO in VEGF-induced plasma protein extravasation. Using a modified Miles assay, intradermal injection in mice ears of VEGF-A(165), VEGF-A(121), and VEGF-C (1 microM) which activate VEGFR-2 (Flk-1) receptor increased vascular permeability, whereas a treatment with VEGFR-1 (Flt-1) analogs; PlGF and VEGF-B (1 microM) had no such effect. Pretreatment of mice with PAF receptor antagonist (LAU8080) or endothelial nitric oxide synthase (eNOS) inhibitor (L-NAME) abrogated protein extravasation mediated by VEGF-A(165). As opposed to PAF (0.01-1 microM), treatment with acetylcholine (ACh; up to 100 microM; inducer of NO synthesis) or sodium nitroprusside (SNP; up to 1 microM; NO donor) did not induce protein leakage. Simultaneous pretreatment of mice with eNOS and protein kinase A (PKA) inhibitors restored VEGF-A(165) vascular hyperpermeability suggesting that endogenous NO synthesis leads to PKA inhibition, which support maintenance of vascular integrity. Our data demonstrate that VEGF analogs increase vascular permeability through VEGFR-2 activation, and that both endogenous PAF and NO synthesis contribute to VEGF-A(165)-mediated vascular permeability. However, PAF but not NO directly increases vascular permeability per se, thereby, suggesting that PAF is a direct inflammatory mediator, whereas NO serves as a cofactor in VEGF-A(165) proinflammatory activities.
...
PMID:Vascular permeability induced by VEGF family members in vivo: role of endogenous PAF and NO synthesis. 1711 9

One of the earliest descriptions of non-neuronal ACh synthesis was by Morris who reported that ACh was synthesized in the placenta [1]; furthermore, Falugi et al. showed the presence of AChE in human fibrosarcoma cells [2]. Afterward, the expression of ACh, AChE, and cholinergic receptors in non-neuronal cells was reported in several studies [3-16]. Indeed, recent data reported that SCLC expresses a cholinergic autocrine loop that can regulate cell growth. Such work demonstrates that SCLC cells have a cholinergic phenotype and that ACh exerts as an autocrine growth factor in human lung tumours [16]. Moreover, it has been recently reported that nicotine in lung adenocarcinoma A549 cells, potently induces Bad phosphorylation at serine (S)112, S136 and S155 in a mechanism involving activation of MAPKs, ERK1/2, PI3K/AKT and PKA through the linking to alpha7-receptors [9]. Bad phosphorylation results in sequestering Bad from mitochondria and subsequently interacting with 14-3-3 in the cytosol [9]. We have recently reported that human malignant pleural mesothelioma expresses a cholinergic system, involved in cell growth regulation. Hence, mesothelioma cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) have a proliferative effect and antagonists (i.e. curare or alpha-cobratoxin) have an inhibitory effect. Furthermore apoptosis mechanisms are under the control of the cholinergic system (nicotine antiapoptotic via induction of NF-kappaB complexes and phosphorylation of Bad at S112, curare proapoptotic via G0-G1 arrest p21waf-1-dependent, but p53-independent) [16]. The involvement of the non-neuronal cholinergic system in lung cancer and mesothelioma appears reasonable and opens up new translational research strategies.
...
PMID:Development of novel therapeutic strategies for lung cancer: targeting the cholinergic system. 1716 19

The neuronal nicotinic acetylcholine receptor (nAChR) alpha4 and beta2 subunits expressed in heterologous expression systems assemble into high- and low-affinity receptors (Zwart and Vijverberg, 1998; Buisson and Bertrand, 2001; Houlihan et al., 2001; Nelson et al., 2003), which reflects the assembly of two distinct subunit stoichiometries of alpha4beta2 receptor (Nelson et al., 2003). The high-affinity receptor ([alpha4]2[beta2]3) is about 100-fold more sensitive to ACh than the low-affinity receptor ([alpha4]3[beta2]2) (Zwart and Vijverberg, 1998; Buisson and Bertrand, 2001; Houlihan et al., 2001; Nelson et al., 2003). Recent evidence implicated 14-3-3 proteins as modulators of the relative abundance of nAChR subunits in the endoplasmic reticulum (ER), where ligand-gated ion channels assemble. The 14-3-3 proteins influence ER-to-plasma membrane trafficking of multimeric cell-surface proteins (O'Kelly et al., 2002). 14-3-3 proteins bind components of these multimeric proteins, and this interaction overrides dibasic COP1 retention signal to permit forward transport of the protein (O'Kelly et al., 2002). In the case of alpha4beta2 nAChRs, 14-3-3 binds the alpha4 subunit, and this association is dependent on phosphorylation of a serine residue within a protein kinase A(PKA) consensus sequence in the large cytoplasmic domain of the alpha4 subunit, which is also a binding motif recognized by 14-3-3 (Jeancloss et al., 2001; O'Kelly et al., 2002). The interplay among PKA, alpha4 subunits, and 14-3-3 proteins increases cell-surface expression of alpha4beta2 nAChRs by increasing steady-state levels of the alpha4 subunit available for assembly with beta2 subunits (Jeancloss et al., 2001). Because it is not known how 14-3-3-dependent changes in the steady-state levels of the alpha4 subunit might affect the functional type of alpha4beta2 receptors, we have investigated the effects of mutations of the 14-3-3 binding motif in the alpha4 subunit on alpha4beta2 nAChR function.
...
PMID:Phosphorylation and function of alpha4beta2 receptor. 1719 45

The objectives of this study were to determine the effects of chronic treatment with pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the impaired endothelium-dependent relaxation seen in aortas from established streptozotocin (STZ)-induced diabetic rats, and to identify some of the molecular mechanisms involved. Starting at 8 weeks of diabetes, pioglitazone (10 mg/kg) was administered to STZ-induced diabetic rats for 4 weeks. In untreated STZ rats (vs age-matched control rats): (1) ACh-induced relaxation, cGMP accumulation, phosphorylation of the cGMP-dependent protein kinase substrate vasodilator-stimulated phosphoprotein at Ser-239 [an established biochemical end-point of nitric oxide (NO)/cGMP signaling], and Cu/Zn-superoxide dismutase (SOD) expression and SOD activity were all reduced; (2) aortic superoxide generation, nitrotyrosine expression, and NAD(P)H oxidase activity were increased; (3) plasma endothelin-1 (ET-1) and aortic c-Jun (AP-1 component) protein expressions were increased. Pioglitazone treatment markedly corrected the above abnormalities. Collectively, these results suggest that pioglitazone treatment improves endothelium-dependent relaxation by reducing oxidative stress via increased SOD activity, decreased NAD(P)H oxidase activity, and a decreased ET-1 level, and that this decreased ET-1 level may be attributable to an inhibition of the AP-1 signaling pathway.
...
PMID:Mechanisms underlying the chronic pioglitazone treatment-induced improvement in the impaired endothelium-dependent relaxation seen in aortas from diabetic rats. 1734 27

The use of binomial analysis as a tool for determining the sites of action of neuromodulators may be complicated by the nonuniformity of release probability. One of the potential sources for nonuniformity of release probability is the presence of multiple forms of synaptotagmins, the Ca2+ sensors responsible for triggering vesicular exocytosis. In this study we have used Sr2+, an ion whose actions may be restricted to a subpopulation of synaptotagmins, in an attempt to obtain meaningful estimates of the binomial parameters p (the probability of evoked acetylcholine [Ach] release) and n (the immediate available store of ACh quanta, whereby m = np). In contrast to results in Ca2+ solutions, binomial analysis of Sr2+-dependent release reveals a dramatically reduced dependence of n on extracellular Sr2+ concentrations. In Sr2+ solutions, blockade of potassium channels with 3,4-diaminopyridine increased m by an exclusive increase in p, whereas treatment with phorbol ester increased m solely by effects on n. The cyclic adenosine monophosphate (cAMP) analogue CPT-cAMP increased m by increasing both n and p. The effect of CPT-cAMP on p but not on n was blocked by protein kinase A (PKA) inhibitors, whereas the effect on n was mimicked by 8-CPT-2'-O-Me-cAMP, a selective agonist for exchange protein directly activated by cAMP, otherwise known as the cAMP-sensitive guanine nucleotide-exchange protein. The results demonstrate both the utility of the binomial distribution in Sr2+ solutions and the dual effects of cyclic AMP on both PKA-dependent and PKA-independent processes at the amphibian neuromuscular junction.
...
PMID:Mechanisms of neuromodulation as dissected using Sr2+ at motor nerve endings. 1838 84

At the mouse neuromuscular junction, activation of adenosine A(1) and P2Y receptors inhibits acetylcholine release by an effect on voltage dependent calcium channels related to spontaneous and evoked secretion. However, an effect of purines upon the neurotransmitter-releasing machinery downstream of Ca(2+) influx cannot be ruled out. An excellent tool to study neurotransmitter exocytosis in a Ca(2+)-independent step is the hypertonic response. Intracellular recordings were performed on diaphragm fibers of CF1 mice to determine the action of the specific adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentyl-adenosine (CCPA) and the P2Y(12-13) agonist 2-methylthio-adenosine 5'-diphosphate (2-MeSADP) on the hypertonic response. Both purines significantly decreased such response (peak and area under the curve), and their effect was prevented by specific antagonists of A(1) and P2Y(12-13) receptors, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and N-[2-(methylthioethyl)]-2-[3,3,3-trifluoropropyl]thio-5'-adenylic acid, monoanhydride with dichloromethylenebiphosphonic acid, tetrasodium salt (AR-C69931MX), respectively. Moreover, incubation of preparations only with the antagonists induced a higher response compared with controls, suggesting that endogenous ATP/ADP and adenosine are able to modulate the hypertonic response by activating their specific receptors. To search for the intracellular pathways involved in this effect, we studied the action of CCPA and 2-MeSADP in hypertonicity in the presence of inhibitors of several pathways. We found that the effect of CPPA was prevented by the calmodulin antagonist N-(6-aminohexil)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) while that of 2-MeSADP was occluded by the protein kinase C antagonist chelerythrine and W-7. On the other hand, the inhibitors of protein kinase A (N-(2[pbromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide, H-89) and phosphoinositide-3 kinase (PI3K) (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride, LY-294002) did not modify the modulatory action in hypertonicity of both purines. Our results provide evidence that activation of A(1) and P2Y(12-13) receptors by CCPA and 2-MeSADP inhibits ACh release from mammalian motor nerve terminals through an effect on a Ca(2+)-independent step in the cascade of the exocytotic process. Since presynaptic calcium channels are intimately associated with components of the synaptic vesicle docking and fusion processes, further experiments could clarify if the actions of purines on calcium channels and on secretory machinery are related.
...
PMID:Effect of purines on calcium-independent acetylcholine release at the mouse neuromuscular junction. 1853 62


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

---