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)

This study examines the involvement of hormones and neuromediators in the regulation of Na+, K+, Cl- cotransport in renal epithelial cells using Madin-Darby canine kidney cells with low transepithelial electrical resistance (194+/-47 Omega/cm2). In this cell line, Na+, K+, Cl- cotransport measured as bumetanide-sensitive 86Rb influx was inhibited up to 50-60% with agonists of P2-purinoceptors (ATP approximately ADP>UTP>AMP), slightly (15-30%) increased by activators of cAMP signaling (forskolin, 8-Br-cAMP) and was insensitive to activators of cGMP signaling (8-Br-cGMP, nitroprusside), EGF, angiotensin II, bradykinin, methacholine, propranolol, vasopressin, adenosine, dopamine and histamine. Thirty min of preincubation of MDCK cells with 0.1 microM PMA completely blocked the activity of Na+, K+, Cl- cotransport whereas down-regulation of this enzyme by 24 h of preincubation with 1 microM PMA activated Na+, K+, Cl- cotransport by 60% and abolished the effect of short-term treatment with PMA. Regulation of Na+, K+, Cl- cotransport by ATP was insensitive to down-regulation of PMA-sensitive isoforms of protein kinase C. In addition, an inhibitor of protein kinase activity, staurosporine, abolished the effect of 0.1 microM PMA but did not change inhibition of this carrier by ATP. Thus, these results show for the first time that P2-purinoceptors and PMA-sensitive isoforms of protein kinase C play a key role in the regulation of Na+, K+, Cl- cotransport in MDCK cells. These results also show that neither PMA- nor staurosporine-sensitive forms of protein kinase are involved in the inhibition of Na+, K+, Cl- cotransport by activators of P2-purinoceptors.
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PMID:Complete inhibition of Na+, K+, Cl- cotransport in Madin-Darby canine kidney cells by PMA-sensitive protein kinase. 951 30

Pituitary adenylate cyclase-activating polypeptide (PACAP) causes both Ca2+ release and Ca2+ influx in bovine adrenal chromaffin cells. To elucidate the mechanisms of PACAP-induced Ca2+ release, we investigated expression of PACAP receptors and measured inositol trisphosphates (IP3), cyclic AMP, and the intracellular Ca2+ concentration in bovine adrenal medullary cells maintained in primary culture. RT-PCR analysis revealed that bovine adrenal medullary cells express the PACAP receptor hop, which is known to couple with both IP3 and cyclic AMP pathways. The two naturally occurring forms of PACAP, PACAP38 and PACAP27, both increased cyclic AMP and IP3, and PACAP38 was more potent than PACAP27 in both effects. Despite the effects of PACAP on IP3 production, the Ca2+ release induced by PA-CAP38 or by PACAP27 was unaffected by cinnarizine, a blocker of IP3 channels. The potencies of the peptides to cause Ca2+ release in the presence of cinnarizine were similar. The Ca2+ release induced by PACAP38 or by PACAP27 was strongly inhibited by ryanodine and caffeine. In the presence of ryanodine and caffeine, PACAP38 was more potent than PACAP27. PACAP-induced Ca2+ release was unaffected by Rp-adenosine 3',5'-cyclic monophosphothioate, an inhibitor of protein kinase A. Ca2+ release induced by bradykinin and angiotensin II was also inhibited by ryanodine and caffeine, but unaffected by cinnarizine. Although IP3 production stimulated by PACAP38 or bradykinin was abolished by the phospholipase C inhibitor, U-73122, Ca2+ release in response to the peptides was unaffected by U-73122. These results suggest that PACAP induces Ca2+ release from ryanodine/caffeine stores through a novel intracellular mechanism independent of both IP3 and cyclic AMP and that the mechanism may be the common pathway through which peptides release Ca2+ in adrenal chromaffin cells.
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PMID:Pituitary adenylate cyclase-activating polypeptide causes Ca2+ release from ryanodine/caffeine stores through a novel pathway independent of both inositol trisphosphates and cyclic AMP in bovine adrenal medullary cells. 952 83

Several cytokines and LPS regulate the population of the B1 receptors (B1Rs) for kinins; these are responsive to des-Arg9-bradykinin (BK) and Lys-des-Arg9-BK. B1R activation contributes to inflammatory vascular changes and pain. Aortic rings isolated from normal rabbits and incubated in vitro in Krebs physiological medium were used as a model of tissue injury. From a null level of response, these rings exhibit a time- and protein synthesis-dependent increase in the maximal contractile response to des-Arg9-BK. Exposure to exogenous IL-1beta or epidermal growth factor (EGF) considerably increases the process of sensitization to the kinins. Freshly isolated control aortic rings showed high mitogen-activated protein (MAP) kinase activities (persistent activation of p38, but less prolonged for extracellular signal-regulated kinase and c-Jun-N-terminal kinase/stress-activated protein kinase pathways) relatively to the basal activities found in various types of cultured cells. IL-1beta or EGF further increased the activities of the extracellular signal-regulated kinase and c-Jun-N-terminal kinase/stress-activated protein kinase MAP kinases. The inhibitor of the p38 MAP kinase, SB 203580 (10 microM), massively (approximately 75%) and selectively inhibited the spontaneous sensitization to des-Arg9-BK over 6 h. SB 203580 also significantly reduced the development of the response to des-Arg9-BK as stimulated by IL-1 or EGF. Both spontaneous and IL-1beta-stimulated up-regulation of responsiveness to des-Arg9-BK were significantly inhibited by the MAP kinase extracellular signal-regulated kinase kinase 1 inhibitor PD 98059 (approximately 40%). The protein kinase inhibitors failed to inhibit protein synthesis and to acutely inhibit the contractile effect of des-Arg9-BK, suggesting that they do not influence B1 receptor transduction mechanisms. In cultured aortic smooth muscle cells stimulated with EGF, MAP kinase activation preceded B1R mRNA induction. Protein kinase inhibitors reveal the role of cell injury-controlled MAP kinase pathways, and singularly of the p38 pathway, in the induction of B1R.
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PMID:Role of the mitogen-activated protein kinases in the expression of the kinin B1 receptors induced by tissue injury. 957 May 62

Recently identified c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase are activated by stimuli of various cellular stresses, cytokines, and growth factors. Strong activation of JNK was reported in the regenerating liver, implicating JNK in growth stimulation of hepatocytes. However, it is not known which factors regulate JNK activity in liver cells. In this study, we examined activation of JNK and p38 in HepG2 cells stimulated with heterotrimeric G protein-coupled receptor agonists known as mitogens. Thrombin, lysophosphatidic acid (LPA), and bradykinin (BK) stimulated extracellular signal-regulated protein kinase to similar extents, indicating that HepG2 cells have cell surface receptors for these agonists, which are coupled to intracellular signaling pathways. In contrast, only thrombin strongly activated JNK and p38. Thrombin-induced activation of JNK and p38 peaked at 30 minutes and 15 minutes with maximal stimulation of 13- and 4-fold increases, respectively. LPA and BK failed to activate JNK at all and activated p38 only slightly. Interestingly, thrombin-induced JNK activation was inhibited by protein kinase C down-regulation and the addition of a specific protein kinase C inhibitor. Short-term stimulation of cells with an active phorbol ester also induced JNK activation in HepG2 cells. These results indicate that thrombin is a relatively strong activator for JNK and p38 and might play a role in the regulation of activities of JNK and p38 in liver cells.
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PMID:Thrombin activates two stress-activated protein kinases, c-Jun N-terminal kinase and p38, in HepG2 cells. 958 92

The regulation of transport of the fluorescent organic cation 4-(4-dimethylaminostyryl)-N-methylpyridinium (ASP+) by renal proximal tubular organic cation transport was studied in IHKE-1 and LLC-PK1 cells with a recently established fluorometric technique (Stachon et al., 1996, 1997). Stimulation of Ca++/diacylglycerol-dependent protein kinase by 1,2-dioctanoyl glycerol (DOG; 0.01-1 mumol/l, n = 7), ATP (0.1 mmol/l, n = 9), oxytocin (0.1 mumol/l, n = 6) and bradykinin (1 mumol/l, n = 7) resulted in an increase of ASP+ accumulation in IHKE-1 cells by 35 +/- 9% (DOG), 65 +/- 30% (ATP), 66 +/- 14% (bradykinin) and 70 +/- 20% (oxytocin) as compared with basal conditions, whereas ASP+ accumulation was slightly reduced in LLC-PK1 cells after stimulation with DOG (1 mumol/l, -20 +/- 7%, n = 10) and angiotensin II (0.1 nmol/l, -20 +/- 5%, n = 6). ASP+ accumulation in IHKE-1 cells also was increased by 0.5 mumol/l (20 +/- 8%, n = 8) and 1 mumol/l forskolin (35 +/- 13%, n = 19), and by 8-bromo-cAMP (1 mumol/l, 125 +/- 25%, n = 9), both activators of the cAMP-dependent protein kinase (PKA). Activation of the cGMP-dependent protein kinase (PKG) by human atrial natriuretic peptide (10 nmol/l, n = 10) or 8-bromo-cGMP (0.1 mmol/l, n = 12) resulted in an increase of 35 +/- 5% and 28 +/- 6%, respectively. Activation of PKA and PKG had no influence on ASP+ transport in LLC-PK1 cells. Regulation of ASP+ uptake by these two cell lines may be caused by direct phosphorylation of the organic cation transporters involved or by regulation of trafficking of the transporters to the membrane. Differences in the organic cation transporter isoforms or alternatively, in the trafficking may contribute to the distinct regulation of ASP+ transport in IHKE-1 and LLC-PK1 cells.
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PMID:Regulation of organic cation transport in IHKE-1 and LLC-PK1 cells. Fluorometric studies with 4-(4-dimethylaminostyryl)-N-methylpyridinium. 965 73

The effect of activation of the Ca2+-sensing receptor on net Cl flux (JCl) has been investigated on microperfused cortical (C) thick ascending limb (TAL) from rat kidney. Increasing bath Ca2+ from 0.5 to 3 mM or adding 200 microM of the specific Ca2+-sensing receptor agonist neomycin reduced basal as well as antidiuretic hormone (ADH)-stimulated JCl by 27.7 +/- 5.0% and 25.9 +/- 4.1%, respectively. JCl remained unchanged in time control tubules. The effect of neomycin/Ca2+ on JCl was blocked by two protein kinase A inhibitors, H-9 or H-89, but not by a protein kinase C inhibitor, GF-109203X, regardless of whether ADH was present or not. Moreover, H-89 decreased basal JCl and prevented a further effect of 3 mM Ca2+. When JCl was increased by 8-bromo-cAMP plus IBMX, no effect of 3 mM Ca2+ was observed. Inhibitors of phospholipase A2 and cytochrome P-450 monooxygenase failed to modify the effect of 3 mM Ca2+, although these agents dampened significantly the inhibitory effect of bradykinin on medullary TAL. We conclude that extracellular Ca2+ decreases basal and ADH-stimulated Cl reabsorption in CTAL by inhibiting the cAMP pathway, independently of protein kinase C or phospholipase A2 stimulation.
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PMID:Extracellular Ca2+ decreases chloride reabsorption in rat CTAL by inhibiting cAMP pathway. 969 Oct 8

We studied the mechanisms of retinal and choroidal vasorelaxation elicited by nitric oxide (NO) using piglet eyes. The NO donors sodium nitroprusside (SNP) and diethylamine-NONOate caused comparable concentration-dependent relaxation that was partially (approximately 40%) attenuated by the guanylate cyclase inhibitors methylene blue and LY83583 and reduced to a lesser extent (approximately 25%) by the inhibitor of cGMP-dependent kinase, KT 5823. In contrast, NO-induced dilatation (by NO donors and endogenous NO after stimulation with bradykinin) was substantially (approximately 70%) diminished by the KCa channel blockers tetraethylammonium (TEA), charybdotoxin, and iberiotoxin; by the cyclooxygenase inhibitors indomethacin and ibuprofen; by the prostaglandin I (PGI2) synthase inhibitor trans-2-phenyl cyclopropylamine (TPC); and by the removal of endothelium; whereas relaxation of endothelium-denuded vasculature to SNP was unaltered by indomethacin, TPC, and charybdotoxin but was nearly nullified by methylene blue and the Kv channel blocker 4-aminopyridine. NO donors significantly increased PGI2 synthesis and the putative PGI2 receptor-coupled second messenger cAMP, from ocular vasculature (retinal microvessels and choroidal perfusate), and this increase in PGI2 formation was markedly reduced by TPC, tetraethylammonium, charybdotoxin, and/or the removal of endothelium, but it was only slightly reduced by methylene blue and LY83583. Also, SNP and KCa channel openers NS1619 and NS004 caused an increase in PGI2 synthesis in cultured endothelial cells, which was virtually abolished by KCa blockers. Finally, vasorelaxation to a cGMP analogue, 8-bromo cGMP, and protein kinase G stimulant beta-phenyl-1,N2-etheno-8-bromoguanosine 3':5'-cyclic monophosphate was mostly Kv dependent and, in contrast to NO, largely unrelated to PGI2 formation. In conclusion, data indicate that NO-induced ocular vasorelaxation is partly mediated by cGMP through its action on smooth muscle, and more importantly, by stimulating PGI2 formation of endothelial origin via a mechanism mostly independent of guanylate cyclase, which involves the opening of a KCa channel.
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PMID:A major role for prostacyclin in nitric oxide-induced ocular vasorelaxation in the piglet. 975 42

We studied the mechanisms underlying the bradykinin-evoked changes in intracellular calcium concentration ([Ca2+]i) in Madin Darby canine kidney (MDCK) cells. Bradykinin evoked a [Ca2+]i transient in a dose-dependent manner, measured by fura-2 fluorimetry and digital video imaging. The transient consisted of a rise and a decay and [Ca2+]i returned to baseline without oscillations. External Ca2+ influx occurred, as demonstrated by Mn2+ quench and external Ca2+ removal measurements. Bradykinin acted by stimulating bradykinin B2 receptors as evidenced by blockade by D-arginyl-L-arginlyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl -3-(2-thienyl)-L-alanyl-L-seryl-D-1,2,3,4-tetrahydro-3-isoquinolineca rbonyl-L-(2alpha,3beta,7alphabeta)-octahydro-1 H-indole-2-carbonyl-L-arginine (HOE 140) but not by D-arginyl-L-arginlyl-L-prolyl-trans-4-hydroxy-L-proylglycyl- 3-(2-thienyl)-L-alanyl-L-seryl-D-1,2,3,4-tetrahydro-3-isoquinolinecar bonyl-L-(2alpha,3beta,7alphabeta)-octahydro-1 H-indole-2-carbonyl ([Des-Arg]HOE 140). The [Ca2+]i signal was abolished by 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1 H-pyrrole-2,5-dione (U73122) and partially inhibited by neomycin, implying mediation by phospholipase C. The transient was initiated by a release of Ca2+ from internal stores since it was abolished by pretreatment with thapsigargin or cyclopiazonic acid. The mobilization of the internal Ca2+ store subsequently triggered a 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1 H-imidazole hydrochloride (SKF 96365)-insensitive Ca2+ entry. Pretreatment with carbonylcyanide m-chlorophynylhydrozone and gly-phe-beta-naphthylamide did not alter the transient, thus excluding the participation of mitochondria and lysosomes. Efflux via Ca2+ pumps contributed to the decay of the transient. Efflux via Na+/Ca2+ exchange or sequestration by mitochondria and lysosomes was insignificant. The transient was blunted by the protein kinase C activator phorbol 12-myristate 13-acetate, and was enhanced by the protein kinase C inhibitors sphingosine and chelerythrine, the protein kinase A inhibitor 2,5-di-(t-butyl)-1,4-hydroquinone, N-[2-(p-bromocinnamylamino)ethyl]5-isoquinolinesulfonamide (H-89), the agent 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate (TMB-8), and agents that elevated levels of 3',5'-cyclic guanosine monophosphate. The transient did not heterologously desensitize with that evoked by ATP, ADP or UTP.
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PMID:Bradykinin-evoked Ca2+ mobilization in Madin Darby canine kidney cells. 976 37

Several kinases have been shown to phosphorylate tau protein at Ser-262, an important site involved in the regulation of the binding of tau to microtubules. In this study we compared the phosphorylation of tau at Ser-262 by CaMKII, PhK and PKA in vitro as determined by radioimmunoblots developed by the monoclonal antibody 12E8 which recognizes P-Ser-262 and P-Ser-356; and Ab-262, a polyclonal antibody which is specific to unphosphorylated Ser-262 in tau. We found that the phosphorylation at Ser-262 was several times more effective by CaMKII than PKA or PhK. Employing rat brain extract as a source of all brain kinases and KN-62, a specific inhibitor of CaMKII, we found that CaMKII accounts for approximately 45% of phosphorylation at Ser-262. Furthermore, in rat brain slices kept metabolically active in oxygenated artificial CSF, phosphorylation of tau at Ser-262 was (i) increased up to 120% in the presence of bradykinin, a CaMKII activator, and (ii) inhibited by approximately 35% in the presence of KN-62. Thus, CaMKII is a major tau Ser-262 kinase in mammalian brain.
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PMID:Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK. 980 Nov 71

Modulatory effects of the activation of either protein kinase C (PKC) by phorbol 12,13-dibutyrate (PDBu) or protein kinase A (PKA) by forskolin on stimulant-evoked secretory processes in the perfused rat adrenal medulla were studied. PDBu or forskolin was applied during repetitive stimulation (30 s each at 10-min intervals) with nicotine, bradykinin, muscarine or histamine, and changes in [Ca2+]i (fura-2 microfluorometry) and catecholamine secretions (electrochemical detection) were simultaneously measured. PDBu markedly potentiated the nicotine-evoked secretion without altering the [Ca2+]i response. PDBu partially inhibited the muscarine-evoked secretion and almost completely blocked the histamine-evoked secretion, concomitantly with extensive suppressions of the [Ca2+]i responses to these stimulants. The bradykinin-evoked secretion was enhanced by PDBu despite a slight attenuation of the [Ca2+]i response. PDBu reduced bradykinin-induced intracellular Ca2+ release in a Ca2+-free medium but enhanced the secretion associated with the released Ca2+. These results suggest that PDBu-activated PKC modulates secretory processes at, at least, two different stages. An early-stage modulation may downregulate receptor/G protein systems, which accounts for the inhibitory effect of PDBu on the muscarine- and histamine-evoked responses. A late-stage modulation may generally promote Ca2+-triggered exocytosis after elevation of [Ca2+]i, which explains the potentiation of the nicotine-evoked secretion by PDBu. The late-stage modulation may counteract the early-stage modulation in bradykinin-stimulated cells. Forskolin potentiated the secretory responses to the four secretagogues without increasing the [Ca2+]i responses. PKA may modulate secretory process at a step(s) distal to the rise in [Ca2+]i as is the case with the late-stage modulation by PKC.
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PMID:Modulations of early and late secretory processes by activation of protein kinases in the rat adrenal medulla. 987 52


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