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)

The relationship between cAMP-dependent protein kinase activity and epinephrine-produced activation of phosphorylase and increase in contractility was investigated in the intact working rat heart. Epinephrine was administered as a bolus into the superior vena cava of open-chest preparations and the hearts were rapidly frozen. cAMP increased within 5 s and returned to control within 20-30 s. Protein kinase and phosphorylase kinase activity ratios increased transiently with the same time course as that for cAMP. The phosphorylase activity ratio and the rate of left ventricular pressure development increased maximally within 15 s and returned to control in 30-60 s. Continuous infusion of epinephrine caused a sustained elevation of the protein kinase. Free catalytic protein kinase activity increased proportionately with the dose of epinephrine. The beta-adrenergic blocking agent, practolol, had no effect on the basal levels of the five parameters studied, but did prevent the epinephrine-produced increases. The results suggest that the time course of cAMP-dependent protein kinase activation is appropriate if this enzyme is to play a role in the catecholamine-induced increase in both glycogenolysis and contractility in the in vivo heart.
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PMID:Protein kinase regulation of cardiac phosphorylase activity and contractility. 20 58

A protein kinase which depends on the simultaneous presence of Ca2+ and the modulator protein for its histone phosphorylation activity has been demonstrated in rabbit skeletal muscle and partially purified. The purified enzyme was not activated by cAMP, cGMP, or incubation with trypsin. Nor was the enzyme inhibited by the protein inhibitor of cAMP-dependent protein kinase. In addition to histone, myosin light chains and phosphorylase kinase served as substrates for the protein kinase, and their phosphorylation also depended on the presence of Ca2+ and the modulator protein. The phosphorylation of phosphorylase kinase was accompanied with a marked activation of the enzyme. The results suggest that the protein kinase has multiple functions and may be involved in the mediation of Ca2+ effects in many biological processes. It is proposed that this enzyme be designated as the modulator-dependent protein kinase. The modulator-dependent protein kinase may be identical to the myosin light chain kinase; chicken gizzard light chain kinase has been shown activatable by the modulator protein (Dabrowska, R., Sherry, J. M. F., Aramatorio, D. K., and Hartshorne, D. J. (1978) Biochemistry 17, 253-258).
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PMID:The modulator-dependent protein kinase. A multifunctional protein kinase activatable by the Ca2+-dependent modulator protein of the cyclic nucleotide system. 20 40

The role of cyclic nucleotides in mediating hormonally responsive adenylate cyclase and cAMP-dependent protein kinase was examined in vivo and in vitro when pseudopregnant rats were injected with hCG. Intracellular ovarian levels of cAMP increased, as expected, but no change in cGMP concentrations was observed. However, both cGMP and cAMP activated ovarian CDPK holoenzyme in vitro but cGMP had a lower affinity. The subunits of hCG were without effect. Even though cGMP and cAMP dissociate partially purified ovarian CDPK holoenzyme in vitro, the receptor sites of the regulatory subunit of CDPK would appear to be relatively specific for cAMP. Moreover, cGMP probably does not mediate hCG action in vivo.
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PMID:Role of cyclic nucleotides in modulating ovarian hCG action. 20 12

Epinephrine rapidly activates phosphorylase in hepatocytes, mainly by a mechanism(s) involving alpha-adrenergic and not beta-adrenergic receptors. The alpha-adrenergic mechanism does not involve accumulation of cAMP or activation of cAMP-dependent protein kinase. It is impaired when hepatocytes are depleted of calcium by EGTA treatment and is rapidly restored by readdition of calcium. Basal phosphorylase is also lowered by calcium deficiency and rapidly increased by calcium but not other divalent cations. The divalent cation ioniphore A23187 increases phosphorylase a levels in hepatocytes in a calcium-dependent manner. Calcium deficiency does not modify the effects of glucagon, cAMP, or beta-adrenergic activation on phosphorylase. Activation of alpha-adrenergic receptors rapidly increases 45Ca fluxes in hepatocytes. Glucagon produces similar effects, but supraphysiological concentrations are required. The hypothesis is advanced that alpha-adrenergic activation of phosphorylase involves alterations in cell calcium such that there is an increase in cytosolic Ca2+ concentration leading to increased phosphorylase kinase activity. Epinephrine induces greater cAMP accumulation in calcium-depleted cells than in normal cells. The effect is mediated by alpha-adrenergic and not beta-adrenergic receptors. Calcium deficiency also cuases cAMP accumulation in hepatocytes incubated with phenylephrine but does not modify the responses of the cells to isoproterenol, glucagon, or cAMP. Low concentrations of calcium rapidly reverse alpha-adrenergic receptor-mediated cAMP accumulation in calcium-depleted cells. The hypothesis is advanced that calcium normally exerts an inhibitory effect on a linkage between alpha-adrenergic receptors and adenylate cyclase in hepatocytes.
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PMID:Mechanisms of catecholamine actions on liver carbohydrate metabolism. 20 89

The recently discovered heat-stable inhibitor protein of the Ca2+-activated cyclic nucleotide phosphodiesterase (Sharma, R. K., Wirch, E. & Warg, J. H. (1978) J. Biol. Chem., in press) has been purified 238 214-fold from bovine brain extract using an affinity column of the modulator protein--Sepharose 4B conjugate. The purified sample appears to be homogeneous as judged by sodium dodecyl sulphate (SDS) gel electrophoresis. The protein band has a mobility corresponding to that of a polypeptide of molecular weight 68 000. Since the heat-stable inhibitor protein has a molecular weight of 70 000 under nondenaturing conditions, it suggests that it is a monomeric protein. The protein has no inhibitory activity toward the cAMP-dependent protein kinase or protein phosphatase. The purified sample has been tested for various enzyme activities which include ATPase, GTPase, cAMP phosphodiesterase, cGMP phosphodiesterase, 5'-nucleotidase, and protein kinase. None of these activities are exhibited by the purified sample.
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PMID:Purification of the heat-stable inhibitor protein of the Ca2+-activated cyclic nucleotide phosphodiesterase by affinity chromatography. 20 31

S49 lymphoma tissue culture cells arrest in the G1 phase of the cell cycle when treated with agents that elevate endogenous cyclic adenosine 3':5'-monophosphate (cAMP), such as cholera toxin or exogenously added active congeners of cAMP such as N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate (Bt2cAMP). This phenomenon requires that cells contain the appropriate receptors: Mutant cells deficient in adenylyl cyclase fail to arrest in response to cholera toxin, and another mutant that lacks cAMP-dependent protein kinase does not respond to cholera toxin or to Bt2cAMP. The size distribution of cell populations treated with Bt2cAMP changes in a manner that reflects only the perturbation of cell cycle distribution. Arrested G1 cells in particular have the same volume as the G1 cells of an exponentially growing population. When G1 cells that have been arrested by Bt2cAMP are grown in fresh medium free of Bt2cAMP, they begin to reenter S phase after a delay of about 6 hr and do so with pseudo-first-order kinetics, with a half-life of 5 hr. These and other properties previously described suggest that cAMP regulates S49 cell growth by physiologically significant rather than artifactual mechanisms.
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PMID:Regulation of S49 lymphoma cell growth by cyclic adenosine 3':5'-monophosphate. 21 91

A set of 24 ATP analogs modified at various positions of the ATP molecule was used for mapping the ATP-binding site in the free catalytic subunit (C) of cAMP-dependent protein kinase (type I). Ki values for these analogs (of which 23 were shown to be competitive with ATP) were measured and compared with Ki values previously obtained for the same set of analogs upon binding to the undissociated form of the enzyme (R2C2). It was found that modifications at the adenine part of ATP bring about a considerable reduction in affinity between C and the resulting analog. The other parts of the ATP molecule play a less important, though definite, role in the binding of this nucleotide to C. By measuring the effect of each given modification in ATP on its binding to C, and comparing the effect of this modification on the binding of the same analog to R2C2, it was possible to obtain 'specificity profiles' for both forms of the kinase. Using such profiles it is shown that the adenine-binding subsite in C may well coincide with the adenine-binding subsite in R2C2. Two plausible models describing the spatial relationship between the ATP sites in C and R2C2 are proposed.
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PMID:Mapping the ATP-binding site in the catalytic subunit of adenosine-3':5'-monophosphate-dependent protein kinase. Spatial relationship with the ATP site of the undissociated enzyme. 21 78

Measurements of tissue cyclic AMP (cAMP) concentration, the activity of cAMP-dependent protein kinase and the level of the enzyme's thermostable, macromolecular inhibitor were made on preparations of rat epididymal fat pad from animals fed high fat or high carbohydrate diets. The cAMP concentration from rats adapted to a high lard diet for 14-15 days was 153 +/- 17.8 pmoles/mg protein as opposed to 76 +/- 6.0 found with high glucose diet. No significant difference in total cAMP-dependent protein kinase activity was observed among rats fed high glucose, high lard or laboratory chow, although the enzyme's activity ratio (-cAMP)(+cAMP) was significantly elevated with lard feeding (0.49 +/- 0.02) as opposed to glucose feeding (0.43 +/- 0.01). Crude preparations from lard and glucose fed animals were equivalent in inhibitory activity when tested with enzyme from chow fed animals. Agarose column chromatography separated holoenzyme and C subunit forms of the protein kinase when 500 mM NaCl was present in the elution buffer. Absence of the salt allowed subunit reassociation to occur. Direct addition of NaCl greater than or equal to 75 mM significantly inhibited protein kinase activity. The results indicate that the adipose tissue of rats fed a high lard diet has a higher concentration of cAMP and an increased protein kinase activity ratio than tissue from rats fed a fat free, high glucose diet. Total cAMP-dependent protein kinase activity and the level of a thermostable macromolecular inhibitor remained unchanged.
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PMID:The concentration of cyclic AMP and the activity of cyclic AMP dependent protein kinase and an inhibitor in the adipose tissue of rats fed lard or glucose diets. 21 69

Kinase-negative mutants of S49 mouse lymphoma cells are pleiotropically negative for all known cAMP-mediated responses of S49 cells and yield cell extracts which are deficient in cAMP binding activity and devoid of cAMP-dependent protein kinase activity. In hybrids between kinase-negative and wild-type cells, the mutant phenotype is dominant: the tetraploid hybrids have reduced cAMP-binding activity and undetectable cAMP-dependent kinase activity. The mutant phenotype is attributable to neither a soluble inhibitor of kinase catalytic subunit, nor a defective kinase regulatory subunit acting as an inhibitor, nor a defective catalytic subunit which sequesters regulatory subunits in inactive complexes. We propose that these mutants carry trans-dominant lesions in a regulatory locus responsible for setting intracellular levels of kinase expression.
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PMID:Kinase-negative mutants of S49 mouse lymphoma cells carry a trans-dominant mutation affecting expression of cAMP-dependent protein kinase. 21 23

This study was initiated in order to elaborate further on the mechanism by which epinephrine modulates cardiac function via protein phosphorylation. A membrane fraction has been isolated from freeze-clamped perfused rat heart that contains two phosphoproteins. These proteins have molecular weights of 36,000 (A protein) and 27,000 (B protein). The phosphorylation of the A protein occurs during the equilibration of the heart with inorganic [32P]phosphate. The phosphorylation of the B protein occurs in response to epinephrine. The A and B proteins are apparently identical with two phosphoproteins in enriched preparations of sarcolemma. The protein of the sarcolemma preparation equivalent to the A protein is phosphorylated in vitro by both cAMP-independent and cAMP-dependent protein kinases. The phosphorylation of the protein of the sarcolemma preparation equivalent to the B protein is catalyzed by the cAMP-dependent protein kinase. Thus the patterns of phosphorylation of these proteins in vivo and in vitro are compatible. The phosphorylation of the B protein has been documented in vitro to modulate calcium transport (Will, H., et al. (1973) Acta Biol. Med. Ger. 31, 45-52), but the response to epinephrine in the perfused heart is not apparently coordinated with the catecholamine-induced inotropic effect.
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PMID:Cyclic adenosine monophosphate dependent and independent phosphorylation of sarcolemma membrane proteins in perfused rat heart. 21 27


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