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)

When determined under the usual conditions of an excess of ligand over protein, the concentration of cyclic AMP necessary to activate pure preparations of cyclic AMP-dependent protein kinase (EC 2.7.1.37; ATP:-protein protein phosphotransferase) half-maximally is in the range of 0.2-0.3 muM when casein or glycogen synthetase is used as the substrate, i.e., essentially the same as the concentration of the nucleotide that is found in resting skeletal muscle. The apparent dissociation constant for cyclic AMP bound to the protein kinase is also about 0.2-0.3 muM when measured under similar conditions. The concentration of the protein kinase in muscle is relatively high (0.23 muM), however, and under these conditions the apparent activation constant of the enzyme for cyclic AMP is raised so that an increase in cyclic AMP levels in the tissue would cause a concomitant increase in protein kinase activity over a wide range of nucleotide concentration. As a result, it is unnecessary to invoke compartmentalization of cyclic AMP to explain how it can control protein kinase activity in vivo. Another factor that may increase the effectiveness of changes in cyclic AMP concentration is the heat-stable protein inhibitor of protein kinase that may function to inhibit the activity of nearly all the protein kinase catalytic subunit dissociated by basal concentrations of cyclic AMP. Finally, the near equity between the concentration of cyclic AMP binding sites and the ligand itself provides a potential mechanism whereby agents can affect the total cyclic AMP content without directly affecting adenylate cyclase, cyclic AMP phosphodiesterase, or cyclic AMP transport.
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PMID:Activation of protein kinase by physiological concentrations of cyclic AMP. 437 27

Histamine, vasoactive intestinal polypeptide (VIP), secretin and prostaglandin E2 (PGE2) stimulate cyclic AMP-dependent protein kinase activity in gastric glands isolated from the guinea pig fundus and antrum. The effects are observed in the absence of any cyclic AMP phosphodiesterase inhibitor and maximal stimulation of the protein kinases occurs within 0.5 min of incubation at 20 degrees C. As shown by dose-response studies, VIP is equally potent in the antrum as in the fundus (identical values of the activation constant are found in both types of gland, Ka = 2.5 . 10(-9) M); a similar situation occurs for PGE2 action (but with Ka = 2.0 . 10(-8) M), whereas the potency of histamine is higher in the fundus (ka = 8.0 . 10(-6)M) than in the antrum (Ka = 5.0 . 10(-5) M). Secretin also increases the protein kinase activity ratio but with a 1000 times lower potency than VIP. In fundic glands, histamine (10(-3) M) is the activator of by far the greatest efficacy (increasing protein kinase activity at 4 times of the basal value) as compared with the effect obtained with 10(-6) M PGE2 (2.7 times) and 10(-7) M VIP (1.4 times). In contrast, VIP has greater efficacy (2.3 times) than histamine (2.1 times) in antral glands, whereas PGE2 is equally active in the two parts of the gastric mucosa. In addition, somatostatin (10(-6) M) inhibits partially (30%) and specifically the protein kinase activation stimulated by histamine, whereas it has no effect on VIP- and PGE2-induced activation. The results are consistent with increased cyclic AMP levels in response to these effectors in this system. A physiological role of histamine on acid-secreting parietal cells, of VIP on nonparietal cells and of PGE2 on both cell types, mediated by the cyclic AMP/protein kinase system is proposed.
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PMID:Differential effects of histamine, vasoactive intestinal polypeptide, prostaglandin E2 and somatostatin on cyclic AMP-dependent protein kinase activation in gastric glands isolated from the guinea pig fundus and antrum. 612 56

Persistent stimulation with isoproterenol of the beta adrenergic receptor located in C6 glioma cell membranes results in a rapid rise in the cyclic AMP content, an activation of soluble cyclic AMP-dependent protein kinase, a translocation of catalytic subunits of the activated protein kinase to the nucleus and a delayed (3--4 hr later) increase of cyclic AMP phosphodiesterase activity and beta-nerve growth factor content. The phosphodiesterase increase requires new RNA and protein synthesis. A pretreatment of the cells with vinblastine in doses that fail to change protein synthesis blocks the increase in phosphodiesterase activity elicited by isoproterenol: the ED50 of vinblastine for this effect is 2.6 x 10(-7) M. In contrast, the simultaneous increase in beta-nerve growth factor content elicited by isoproterenol is not blocked by vinblastine and does not require new RNA and protein synthesis. We conclude that intact microtubules are required to transfer the catalytic subunits of activated protein kinase from cytosol to the nucleus. Hence microtubules may be operative in facilitating communication between the cell membrane and the nucleus.
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PMID:beta Adrenergic receptor-mediated regulation of cyclic nucleotide phosphodiesterase in C6 glioma cells: vinblastine blockade of isoproterenol induction. 624 89

Left pneumonectomy in rats induced growth of the right lung which was maximum one week after the operation. This compensatory lung growth was accompanied by an increase in adenylate cyclase/cyclic AMP phosphodiesterase activity suggesting an increase in the lung adenosine 3',5'-monophosphate (cyclic AMP) levels after pneumonectomy. Activities of cyclic-AMP-dependent protein kinase, phosphorylase and glucose 6-phosphatase were also increased suggesting the enhanced activity of the cascade system (glycogenolysis). Activities of these enzymes were maximally elevated during the first three days of operation and preceded the growth of contralateral lung, returning to the presurgery level on day 14. These data indicate that: (a) the biochemical response to pneumonectomy in rats appeared to be complete in two weeks and, (b) changes in the activities of cyclic-AMP-related enzymes may be important in the compensatory growth of rat lung.
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PMID:Alterations in enzymes related to adenosine 3',5'-monophosphate during compensatory growth of rat lung. 624 52

Imidazole, at concentrations between 10(-3) and 10(-2) M, exerts a profound stimulatory effect on rabbit uterine strips obtained during pregnancy and studied isometrically in vitro. The action is not duplicated by N-alkylimidazoles which have greater potency as inhibitors of thromboxane synthetase but the effect of imidazole was antagonized by isoproterenol or theophylline. Biochemical analysis indicated that imidazole at concentrations greater than 5 x 10(-4) M stimulated both high and low affinity forms of cyclic AMP phosphodiesterase. The uterus of pregnant rabbits is profoundly refractory to any kind of pharmacological stimulation and the effects of imidazole, acting to stimulate phosphodiesterase, suggest that the integrity of the adenyl cyclase-cyclic AMP-protein kinase system is a necessary requirement for this organ to remain quiescent during pregnancy.
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PMID:Enhanced excitability of the uterus of the pregnant rabbit by imidazole stimulation of cyclic AMP phosphodiesterase. 625 37

Cycl AMP concentrations were elevated and acrosome reactions were induced in intact sea urchin spermatozoa by Nigericin, A23187, and pH 9.0 seawater. To determine whether or not the metabolism of cyclic AMP was being altered in sperm heads, the heads were mechanically separated from the flagella, and the flagella-less heads were then isolated by differential centrifugation. The isolated heads contained 1 to 2 nmol of ATP and 1 to 2 pmol of cyclic AMP/mg wet weight and retained these concentrations for several hours if stored at 0 degrees C. The flagella-less heads also retained the mitochondria of the midpiece area. The heads retained their functional status and could be stimulated to undergo acrosome reactions (filament extension) in response to Nigericin, A23187, or pH 9.0 seawater. Furthermore, the isolated heads could activate sea urchin eggs after induction of an acrosome reaction by Nigericin or pH 9.0 seawater. The isolated heads contained appreciable adenylate cyclase, cyclic AMP phosphodiesterase, cyclic GMP phosphodiesterase, guanylate cyclase, cyclic AMP-dependent protein kinase, and calmodulin. Nigericin, pH 9.0 seawater, and A23187 caused not only the induction of an acrosome reaction but also elevations of cyclic AMP in the isolated heads, and extracellular Ca2+ was an absolute requirement for both responses. At 16 degrees C, Nigericin caused elevations of cyclic AMP within 5 s, but maximal elevations were not observed until 1 min; it induced a maximal percentage of acrosome reactions by 40 s. Incubation of cells at 0 degrees C resulted in a delay of maximal acrosome reactions until between 10 and 20 min after addition of Nigericin. Under these conditions, maximal elevations of cyclic AMP were observed by 5 min, demonstrating that cyclic AMP elevations precede the complete morphological change associated with an acrosome reaction. ATP concentrations within the sperm heads declined in response to Nigericin, pH 9.0 seawater, or A23187, and its decrease also required the presence of extracellular Ca2+. The decline in ATP concentrations was slightly more rapid in the presence of rotenone, suggestive of some ATP synthetic capabilities of the isolated head preparation. 45Ca2+ uptake was increased by Nigericin elevated pH, and A23187 but was not appreciably altered by monensin. Monensin also did not cause appreciable elevations of cyclic AMP concentrations, induction of an acrosome reaction, or decreases of ATP concentrations. Here, we describe for the first time that cyclic AMP concentrations can be increased in flagella-less heads of spermatozoa and show that these changes are associated with an acrosome reaction.
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PMID:The elevation of cyclic AMP concentrations in flagella-less sea urchin sperm heads. 625 63

Amrinone is a new noncatechol, nonglycoside agent with cardiotonic and vasodilator properties. This paper examines the effects of amrinone in the toad urinary bladder, a tissue whose function may be altered by many factors which also change cardiovascular activity. Amrinone enhanced the effect of vasopressin and cyclic AMP on water and urea permeabilities, as well as the effect of vasopressin on sodium transport. Consistent with these actions, amrinone inhibited cyclic AMP phosphodiesterase activity in epithelial homogenates and increased both cyclic AMP content and the protein kinase activity ratio measured in intact epithelial cells. The inhibitory effect of amrinone on phosphodiesterase may be relevant to its cardiostimulatory and vasodilator activities.
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PMID:The effects of amrinone on transport and cyclic AMP metabolism in toad urinary bladder. 625 81

Vasoactive intestinal peptide (VIP), secretin, catecholamines and prostaglandin E1 (PGE1) in the presence of a cyclic nucleotide phosphodiesterase inhibitor stimulate the accumulation of cyclic AMP in two colorectal carcinoma cell lines (HT 29 and HRT 18) with subsequent activation of the cyclic AMP-dependent protein kinases. In HT 29 cells incubated without phosphodiesterase inhibitor, 10(-9) M VIP promotes a rapid and specific activation of the lower Km cyclic AMP phosphodiesterase (1.7-fold); at 25 degrees C the effect is maintained for more than 15 min, while at 37 degrees C the activity returns to basal value within 15 min. As shown by dose-response studies, VIP is by far the most effective inducer (Ka equals 4 x 10(-10) M) of the cyclic AMP phosphodiesterase activity; partial activation of the enzyme is obtained by 3 x 10(-7) M secretin, 10(-5) M isoproterenol and 10(-5) M PGE1; PGE2 and epinephrine are without effect. In HRT 18 cells VIP is less active (Ka equals 2 x 10(-9) M) whereas 10(-6) M PGE1, 10(-6) M PGE2 and 10(-5) M epinephrine are potent inducers of th phosphodiesterase activity. The positive cell response to dibutyryl-cyclic AMP further indicates that cyclic AMP is a mediator in the phosphodiesterase activation process. The incubation kinetics and dose response effects of the various agonists on the cyclic AMP-dependent protein kinase activity determined for both cell types in the same conditions show a striking similarity to those of phosphodiesterase. Thus coordinate regulation of both enzymes by cyclic AMP was observed in all incubation conditions.
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PMID:Parallel activation of cyclic AMP phosphodiesterase and cyclic AMP-dependent protein kinase in two human gut adenocarcinoma cells (HT 29 and HRT 18) in culture, by vasoactive intestinal peptide (VIP) and other effectors activating the cyclic AMP system. 626 79

Slow-twitch soleus and fast-twitch extensor digitorum longus muscles of the rat were denervated unilaterally by sciatic nerve section at mid-thigh level. Activities of adenylate cyclase, guanylate cyclase, low Km and high Km cyclic AMP phosphodiesterase, and cyclic GMP phosphodiesterase were compared on the same, freshly prepared homogenates of denervated and shamoperated contralateral muscles one, two, three, or five days after surgery. As an early consequence of denervation, cyclic AMP metabolism was differentially affected in these different types of skeletal muscle. The adenylate cyclase activity of soleus muscle increased significantly by the second day following denervation and continued to rise through the fifth day, while this enzyme did not increase in denervated extensor digitorum longus even by the fifth day. The high Km cyclic AMP phosphodiesterase was already increased by day one in the denervated soleus, but not until the fifth day in the denervated extensor digitorum longus. Parallel increases beginning the first day were observed for the low Km cyclic AMP phosphodiesterase in both muscles. Since the activity of cytosolic cyclic AMP-dependent protein kinase of soleus muscle was also increased two days following denervation, the changes in cyclic AMP synthetic and degradative enzymes apparently result in a rise in intracellular cyclic AMP concentration. Alterations of the cyclic GMP enzymes following denervation were similar in the soleus and extensor digitorum longus, but were delayed relative to the increases in activity in the cyclic AMP enzymes.
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PMID:Effect of denervation on cyclic nucleotide metabolism in different types of skeletal muscle of the rat. 627 85

The recent literature regarding the mechanisms of regulation of lipolysis with emphasis on the role of cyclic nucleotides is reviewed. The following conclusions appear warranted at present. (1) Cyclic AMP (cAMP) is a major regulator of lipolysis. However, mechanisms other than the production and catabolism of cAMP also exist. (2) Insulin can lower adipocyte cyclic AMP levels, but this effect cannot explain all aspects of the antilipolytic effect of insulin. (3) Insulin stimulates cyclic AMP phosphodiesterase and inhibits adenylate cyclase in adipocytes. In addition, there are probably other targets of insulin action. The possibilities include cAMP dependent protein kinase, phosphoprotein phosphatase, and triacylglycerol lipase. (4) Cyclic GMP is probably not directly involved in the regulation of lipolysis. (5) Cytosolic Ca2+ probably plays an important role in the regulation of lipolysis. The nature of such a role for Ca2+ and the potential role of calmodulin in the regulation of lipolysis remain to be explored.
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PMID:Cyclic nucleotides and lipolysis. 627 17


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