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)

We examined the role of protein kinase-C in contractile responses of small arteries of the rat by stimulating and inhibiting protein kinase-C with phorbol myristate acetate and staurosporine, respectively. The experiments were performed in isolated mesenteric resistance arteries that had been sympathectomized and mounted for recording of isometric force development. Phorbol myristate acetate (i) at concentrations lower than 3 nM increased sensitivity for the contractile effect of potassium, but not for the effect of noradrenaline or BAY-K8644, (ii) at concentrations higher than 30 nM increased the sensitivity of depolarized vessels to extracellular calcium and (iii) at concentrations higher than 30 nM induced a contractile effect that depended on the presence of extracellular calcium and that was reduced by the calcium antagonist felodipine. Neither the phorbol ester nor staurosporine affected contractile responses to caffeine in calcium-free solution. Staurosporine (10 nM) reduced the response of resistance arteries to potassium but not to noradrenaline. These results are in agreement with direct observations by others that protein kinase-C plays a role in the activation of voltage-operated calcium channels. Protein kinase-C could participate in this way in electro-mechanical coupling in resistance arterial smooth muscle and, when strongly activated, sensitize the contractile apparatus to calcium.
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PMID:Effects of a phorbol ester and staurosporine on electro- and pharmacomechanical coupling in a resistance artery. 178 1

Normal eukaryotic cells do not initiate mitosis until DNA replication has been completed. This requirement can be bypassed by exposing cells to certain chemicals. We report here that chemically induced premature mitosis is not readily achieved in all mammalian species. Although hamster cells underwent premature mitosis following treatment with caffeine, the protein phosphatase inhibitor okadaic acid, and the protein kinase inhibitors 2-aminopurine and 6-dimethyl-aminopurine, the mouse and human cells examined in this study displayed little or no response to any of these compounds. Differences in cell permeability or metabolism could not account for the species specificity of these drugs, because other biochemical and mitosis-promoting activities were apparent in human cells. Cell-type specificity can be explained, however, by the timing of cyclin B synthesis and p34cdc2/cyclin B complex formation during the cell cycle. Synthesis of cyclin B and formation of a p34cdc2/cyclin B complex, both of which are required for initiation of mitosis, were prevalent in hamster cells arrested in S phase but were absent or barely detectable in arrested human cells. In hamster cells, the hyperphosphorylated form of p34cdc2 was complexed with cyclin B and underwent tyrosine dephosphorylation during caffeine-induced premature mitosis. These findings indicate that the onset of mitosis is regulated somewhat differently among mammalian cell types and that these differences affect the vulnerability of cells to drug-induced mitotic aberrations and cytogenetic damage.
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PMID:Chemically induced premature mitosis: differential response in rodent and human cells and the relationship to cyclin B synthesis and p34cdc2/cyclin B complex formation. 183 Jun 67

1. The properties of intracellular Ca2+ stores of intact- and of saponin-skinned A7r5 (an established cell line from embryonic rat aorta) smooth muscle cells were studied by measuring 45Ca2+ and 54Mn2+ fluxes. 2. Application of 5 microM-vasopressin to intact cells increased the fractional loss of 45Ca2+ in Ca2(+)-free solution by a factor of 5.2. This effect was not influenced by a pre-incubation with 10 microM-ryanodine. Caffeine (25 mM) did not stimulate the fractional loss of 45Ca2+ from intact cells. 3. In skinned cells 10 microM-IP3 (inositol 1,4,5-trisphosphate) and 5 microM-A23187 (a calcium ionophore) released the same amount of 45Ca2+. This release did not require GTP and was not affected by a pre-incubation with 10 microM-ryanodine. Caffeine (25 mM) did not release stored Ca2+. 4. NaF (1 mM) plus 10 microM-AlCl3 inhibited by 72% the 45Ca2+ uptake by the IP3-sensitive store of skinned cells at 0.15 microM-Ca2+. Cyclic AMP-dependent protein kinase did not stimulate this ATP-dependent 45Ca2+ uptake, nor could the presence of phospholamban be demonstrated immunologically. 5. The 45Ca2+ uptake by cells which had been depleted of Ca2+ with 5 microM-vasopressin was 69% higher than the uptake obtained without such proceeding depletion. This enhanced 45Ca2+ uptake did not occur through voltage-operated Ca2+ channels, because blockade of these channels with verapamil, or depolarization of the plasma membrane by increasing [K+] from 5.9 to 59 mM in the presence of verapamil, did not modify this uptake. 6. A similar increase of the 54Mn2+ uptake occurred in intact cells with a depleted Ca2+ store. If, however, the cells were first skinned and subsequently exposed to 54Mn2+, the ATP-dependent 54Mn2+ uptake amounted to less than 6% of the ATP-dependent 45Ca2+ uptake. 7. If intact cells were first exposed to a 45Ca2(+)- or 54Mn2(+)-containing solution, and subsequently skinned in a non-radioactive intracellular solution, the addition of 10 microM-A23187 to these cells released stored Ca2+ or Mn2+. The amount of released Ca2+ was only slightly larger than the amount of released Mn2+. If the intracellular store was depleted before loading, the amount of Ca2+ or Mn2+ released by the ionophore increased by 68 and 28%, respectively. 8. It is concluded that A7r5 smooth muscle cells do not express a Ca2(+)-induced Ca2+ release mechanism, but do contain an IP3-induced Ca2+ release mechanism which can release approximately all intracellularly accumulated 45Ca2+.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Agonist-dependent Ca2+ and Mn2+ entry dependent on state of filling of Ca2+ stores in aortic smooth muscle cells of the rat. 221 95

A subpopulation of canine cardiac sarcoplasmic reticulum vesicles has been found to contain a "Ca2+ release channel" which mediates the release of intravesicular Ca2+ stores with rates sufficiently rapid to contribute to excitation-contraction coupling in cardiac muscle. 45Ca2+ release behavior of passively and actively loaded vesicles was determined by Millipore filtration and with the use of a rapid quench apparatus using the two Ca2+ channel inhibitors, Mg2+ and ruthenium red. At pH 7.0 and 5-20 microM external Ca2+, cardiac vesicles released half of their 45Ca2+ stores within 20 ms. Ca2+-induced Ca2+ release was inhibited by raising and lowering external Ca2+ concentration, by the addition of Mg2+, and by decreasing the pH. Calmodulin reduced the Ca2+-induced Ca2+ release rate 3-6-fold in a reaction that did not appear to involve a calmodulin-dependent protein kinase. Under various experimental conditions, ATP or the nonhydrolyzable ATP analog, adenosine 5'-(beta, gamma-methylene)triphosphate (AMP-PCP), and caffeine stimulated 45Ca2+ release 2-500-fold. Maximal release rates (t1/2 = 10 ms) were observed in media containing 10 microM Ca2+ and 5 mM AMP-PCP or 10 mM caffeine. An increased external Ca2+ concentration (greater than or equal to 1 mM) was required to optimize the 45Ca2+ efflux rate in the presence of 8 mM Mg2+ and 5 mM AMP-PCP. These results suggest that cardiac sarcoplasmic reticulum contains a ligand-gated Ca2+ channel which is activated by Ca2+, adenine nucleotide, and caffeine, and inhibited by Mg2+, H+, and calmodulin.
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PMID:Rapid calcium release from cardiac sarcoplasmic reticulum vesicles is dependent on Ca2+ and is modulated by Mg2+, adenine nucleotide, and calmodulin. 243 95

Here we show the activation of G-protein by inositol trisphosphate (IP3) or caffeine in sarcoplasmic reticulum (SR) of skeletal muscle and the consequent existence of a common mechanism of Ca2+ release from SR induced by caffeine and by IP3. (i) Indomethacin inhibits Ca2+ release induced by IP3 or caffeine. (ii) PGE1 does not induce Ca2+ release itself, but does stimulate Ca2+ release induced by IP3, or caffeine, from SR. (iii) Forskolin stimulates both types of Ca2+ release. The inhibitory effect of indomethacin on both forms of Ca2+ release, and the stimulatory effect of PGE1 and forskolin on either Ca2+ release suggest that there exists a common mechanism between IP3- and caffeine-induced Ca2+ release. (iv) Caffeine or IP3 activates G-protein via inhibition of a GTPase activity. (v) Indomethacin itself inactivates this G-protein by stimulation of a GTPase activity and reverses the activation of G-protein induced by IP3 or caffeine. (vi) PGE1 competes with the inhibitory effect of indomethacin on GTPase activity and PGE1 itself activates G-protein through inhibition of GTPase activity. From these results, it could be suggested that caffeine or IP3 induces Ca2+ release from the SR via activation of G-protein, which affects the Ca2+ channel and cAMP which seems to affect G-protein via A-kinase.
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PMID:A G-protein of sarcoplasmic reticulum of skeletal muscle is activated by caffeine or inositol trisphosphate. 253 55

The purpose of this study was to investigate the effects of the intracellular messenger cyclic GMP (cGMP) on sequestration of cytosolic calcium (Ca2+) into the intracellular Ca2+ store (the sarcoplasmic reticulum) of vascular smooth muscle. Using saponin-skinned primary cultures of rat aortic smooth muscle, we investigated the effect of cGMP on 45Ca uptake in monolayers of cells. The intracellular store was loaded with Ca2+ by exposing the skinned cells to a 45Ca-labeled 1-microM free Ca2+-containing solution for varying durations (0-20 minutes). Addition of 10 microM cGMP to six monolayers increased both the initial Ca2+ uptake at 2 minutes (control, 240 +/- 8 pmol Ca2+/10(6) cells; + cGMP 295 +/- 7; mean +/- SEM; n = 6, p less than 0.01) and the final steady-state uptake reached at 20 minutes (control, 0.96 +/- 0.03 nmol Ca2+/10(6) cells; + cGMP 1.12 +/- 0.03, p less than 0.02). This stimulation of uptake was quantitatively similar to that caused by 10 microM cyclic AMP. It occurred at varying ambient cytosolic Ca2+ concentrations (0.1-1.0 microM Ca2+) and was not further enhanced by addition of 10 microM cGMP-dependent protein kinase. The dose-response of stimulation of Ca2+ uptake with cGMP indicated an ED50 of 5 nM cGMP. The release of Ca2+ from the sarcoplasmic reticulum in response to inositol 1,4,5-trisphosphate or caffeine was unaffected by cGMP. We conclude that the relaxation of vascular smooth muscle with cGMP-producing vasodilators is mediated in part by sequestration of cytosolic Ca2+ by the sarcoplasmic reticulum.
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PMID:Cyclic guanosine monophosphate-enhanced sequestration of Ca2+ by sarcoplasmic reticulum in vascular smooth muscle. 283 13

Methylxanthines are phosphodiesterase inhibitors and are therefore capable of increasing cyclic AMP levels, thereby stimulating cyclic nucleotide-dependent protein kinases. The direct action of several xanthine derivatives on enzyme-dependent phosphorylations involving red blood cell membrane proteins was studied in vitro. Pentoxifylline and caffeine exhibited no effect on the activity of the membrane cAMP-dependent protein kinase. Conversely, methylxanthines proved capable on inhibiting cyclic nucleotide-independent protein kinases present in the membrane and cytosol. This inhibition involves competition with ATP. Comparison of the inhibitory effect of two xanthine derivatives, ie propentofylline and pentoxifylline, demonstrated significant differences. Xanthine derivatives showed no activity on red blood cell tyrosine kinase. Furthermore, three xanthines, ie caffeine, pentoxifylline and propentofylline, inhibited phosphatidylinositol kinase.
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PMID:[Methylxanthines and phosphorylation of the constituents of the membrane of the human red blood cell]. 285 63

Intracellular injection of the catalytic subunit of cAMP-dependent protein kinase stimulated the outward potassium current associated with endogenous cellular Ca2+ which were abolished by either caffeine or cAMP-dependent protein kinase inhibitor. The principal action of this kinase in current activation may be to release calcium from the intracellular reservoir.
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PMID:Cyclic AMP-dependent protein phosphorylation is involved in activation of the potassium current associated with endogenous cellular calcium in Euhadra neurons. 285 88

To investigate the vasodilator actions of nitroglycerine and isoprenaline, the effects of these agents, dibutyryl cyclic AMP (db cyclic AMP) and 8-bromo cyclic GMP (8-Br cyclic GMP) on intact muscle tissue, and cyclic AMP and cyclic GMP on skinned muscle of the rabbit mesenteric artery were investigated. In porcine coronary artery, nitroglycerine (greater than 0.1 microM) increased the production of cyclic GMP with no change in the amount of cyclic AMP, while isoprenaline (greater than 0.1 microM) significantly increased the production of cyclic AMP with no change in the amount of cyclic GMP. In the rabbit mesenteric artery, nitroglycerine or isoprenaline inhibited the tonic component of the 39 mM [K]o-induced contraction to a greater extent than the phasic component. Nitroglycerine and 8-Br cyclic GMP showed a stronger inhibitory action on the K-induced contraction than did isoprenaline and db cyclic AMP. The sources of Ca utilized for the generation of contraction by noradrenaline and caffeine were estimated to be the same as those determined from the amplitudes of contractions evoked in Ca-free solution by various concentrations of noradrenaline or caffeine. In intact muscle tissues, the effects of nitroglycerine or 8-Br cyclic GMP on the amount of Ca stored in cells were estimated from the caffeine-induced contraction in Ca-free solution. Both agents inhibited the contractions due to a reduction in the amount of Ca in the cells. When the effects of isoprenaline or db cyclic AMP were observed, both agents inhibited the caffeine-induced contraction but the accumulation of Ca into cells was greater than the control. In saponin skinned muscles, the pCa-tension relationship in the presence of cyclic AMP and cyclic AMP-dependent protein kinase (cyclic AMP-PK) shifted to the right and to a lower level in comparison with the control. Applications of cyclic GMP with cyclic GMP-dependent protein kinase (cyclic GMP PK) also inhibited the contraction induced by low concentrations of Ca. In skinned muscles, cyclic AMP exhibited dual actions on Ca store sites, i.e. in the presence of high concentrations of Ca or prolonged superfusion of Ca, cyclic AMP reduced the amount of Ca due to activation of the Ca-induced Ca release mechanism by excess accumulation of Ca. On the other hand, cyclic GMP consistently inhibited the amplitude of the caffeine-induced contraction due to a reduction in the amount of Ca in the store sites. 8 These results indicate that nitroglycerine and isoprenaline increase the amount of cyclic GMP and cyclic AMP, respectively. The main effect of cyclic GMP is activation of Ca extrusion, thus reducing the amount of Ca stored in the cell, while the main effect of cyclic AMP is to increase the amount of Ca stored in the cell. Both cyclic AMP with cyclic AMP-PK and cyclic GMP with cyclic GMP-PK inhibit the phosphorylation of myosin. Consequently both cyclic nucleotides reduce the free Ca in the myoplasm and promote relaxation, but by different mechanisms.
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PMID:Nitroglycerine- and isoprenaline-induced vasodilatation: assessment from the actions of cyclic nucleotides. 298 11

Extracellular adenosine 3',5'-cyclic monophosphate (cAMP) is required for cell-type-specific gene expression in developing Dictyostelium discoideum. We have developed a microassay for the expression of these genes, using antibodies directed against their protein products. To characterize the transduction mechanism, we have used in this assay cAMP analogues that preferentially activate either the cell-surface cAMP receptor or the internal cAMP-dependent protein kinase. N6-(aminohexyl) cAMP activates the Dictyostelium cAMP-dependent protein kinase but does not bind to the cell-surface cAMP receptor and does not cause cell-type-specific gene expression. 2'-Deoxy-cAMP does not activate the cAMP-dependent protein kinase but binds to the receptor and causes cell-type-specific gene expression. Cyclic AMP-induced accumulation of prestalk mRNA in shaking cultures still occurs in the presence of caffeine, which blocks the receptor-coupled activation of adenyl cyclase. This suggests that the extracellular cAMP induction of cell-type-specific gene expression in developing Dictyostelium cells is mediated by the cell-surface cAMP receptor and that activating adenyl cyclase by this receptor is not essential. Using the N6-(aminohexyl) cAMP to competitively inhibit phosphodiesterase, we show that 30 nM cAMP is sufficient to induce prestalk or prespore gene expression.
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PMID:cAMP induction of prespore and prestalk gene expression in Dictyostelium is mediated by the cell-surface cAMP receptor. 302 99


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