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)

Guanylate cyclase, cGMP phosphodiesterase and protein kinase activities were determined in kidneys of developing and adult rats. Guanylate cyclase activities of crude kidney homogenates, 100,000 x g supernatant and pellet of 7- and 21-day-old and adult rats were determined (Table I). In the kidneys of 7-day-old rats activity was 162% of adult controls in the homogenates (P less than .001), 144% in the soluble (P less than .005) and 308% in the particulate fraction (P less than .001). In 3-week-old rats activity was still significantly higher at 144% in the homogenate (P less than 0.02) and at 225% in the particulate (P less than .001). Phosphodiesterase activity for cGMP was 7488 +/- 831 pmol cGMP/mg protein . min in 1-week-old and 7674 +/- 1120 in 3-week-old rats vs. 4042 +/- 122 in the adults (P less than .025) (Table II). Chromatography on Sephadex G-200 showed two peaks of cGMP-stimulatable protein kinase in both the adult and newborn kidney and in addition a minor peak of cGMP-stimulatable kinase in the newborn kidny only (Fig. 2).
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PMID:Increases of guanosine 3',5'-monophosphate-related enzymes in kidneys of developing rats. 2 9

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

Compounds containing the imidazoquinoline nucleus are a new class of potent, broad-spectrum inhibitors of platelet aggregation. This report describes studies with a simply-substituted imidazoquinoline (BMY 20844) and several new ether-linked side chain derivatives (BMY 21638 and BMY 43351). These compounds are potent inhibitors of platelet cAMP phosphodiesterase (IC50 values: BMY 20844, 1.3 X 10(-8); BMY 21638, 2 X 10(-10); and BMY 43351, 1 X 10(-10) M, measured using 0.15 microM cAMP) but have little effect on platelet homogenate cGMP phosphodiesterase (IC50 greater than 10(-5) M). Inhibition of different cAMP phosphodiesterase isozymes was tested to determine if the compounds inhibited similar isozymes in other tissues. Rabbit heart cAMP phosphodiesterase isozymes were resolved by ion-exchange chromatography and three peaks of activity were obtained. BMY 20844 inhibited only fraction III (a "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase) with an IC50 value of 5 X 10(-8) M. These compounds also inhibited canine cardiac sarcoplasmic reticulum membrane-bound "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase with virtually the same potency as inhibition of cAMP phosphodiesterase in platelet homogenate. In washed platelets these compounds elevated cAMP levels and activated the platelet cAMP dependent protein kinase. Activation of cAMP-dependent protein kinase was determined by cAMP-dependent protein kinase ratio measurements and phosphorylation of intracellular proteins. These studies suggest that this potent new class of agents inhibits platelet phosphodiesterase activity in intact platelets causing an elevation in cAMP levels sufficient to activate the cAMP-dependent protein kinase and stimulate protein phosphorylation. This mechanism is, at least in part, responsible for the ability of these compounds to prevent platelet aggregation and thrombosis in experimental animal models.
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PMID:Imidazoquinoline derivatives: potent inhibitors of platelet cAMP phosphodiesterase which elevate cAMP levels and activate protein kinase in platelets. 164 98

An inhibitory subunit (P gamma) of cGMP phosphodiesterase from vertebrate rod photoreceptors (frog, toad, and bovine) was phosphorylated by cytosolic protein kinase(s) derived from intact frog rod outer segments. The phosphorylation of frog P gamma was stimulated by phosphatidylinositol but not by cAMP or cGMP. One- and two-dimensional gel electrophoresis revealed that 70-80% of P gamma was phosphorylated with 1 mol of phosphate per frog P gamma under optimal conditions. A peptide that derived from an active domain of bovine P gamma was also phosphorylated. Phosphorylation of frog P gamma was inhibited by addition of the peptide to the reaction mixture. Phosphorylation of frog P gamma was also inhibited by addition of transducin subunits or active (P gamma-less) cGMP phosphodiesterase. Okadaic acid, on the other hand, enhanced P gamma phosphorylation, suggesting the presence of protein phosphatase(s) in the cytosolic fraction. These data suggest another mechanism for the regulation of cGMP phosphodiesterase in vertebrate rod photoreceptors.
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PMID:Phosphatidylinositol-stimulated phosphorylation of an inhibitory subunit of cGMP phosphodiesterase in vertebrate rod photoreceptors. 185 3

Cyclic GMP-binding proteins present in membrane fractions of bovine retina and, in particular, rod outer segments (ROS) were identified by photoaffinity labeling with 8-azido-[32P]cGMP. Two soluble proteins and two membrane-associated proteins were specifically labeled. The soluble proteins, 93 and 72 kDa, corresponded respectively to the alpha subunit of ROS cGMP phosphodiesterase and cGMP-dependent protein kinase. One of the two membrane-associated proteins, 53 kDa, was present in all particulate retinal fractions. Its function is unknown. It is distinct from cAMP-dependent protein kinase or the 63-kDa cGMP-activated channel from ROS. The second membrane-associated protein, 37 kDa, was present only in fractions that did not contain ROS. The molecular mass of this protein was similar to that of a cGMP-binding protein previously attributed to rod cells.
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PMID:Guanosine 3',5'-cyclic nucleotide binding proteins of bovine retina identified by photoaffinity labeling. 215 64

The antigen receptors on B lymphocytes, membrane forms of immunoglobulins, transduce signals regulating B cell growth and differentiation by activating a phosphoinositide-specific phospholipase C. In this report, we describe our recent work aimed at understanding this process in greater detail. We have shown that a GTP-binding component is a necessary cofactor in the stimulation of phospholipase C by mIgM. This component has a number of properties in common with the G protein family of receptor-effector coupling components seen in the adenylate cyclase and other signaling systems. For example, analogues of GTP that cannot be hydrolyzed stimulated mIgM-triggered phosphoinositide breakdown, and an analogue of GDP that cannot be converted to GTP inhibited the reactions. Furthermore, aluminum fluoride, which activates known G proteins, also stimulates phosphoinositide breakdown. The G protein that appears to link mIgM to phospholipase C is not one of the well characterized G proteins involved in the regulation of adenylate cyclase or cGMP phosphodiesterase (GS, Gi, and transducin), as judged by its insensitivity to two bacterial toxins that modify these G proteins, cholera toxin and pertussis toxin. Interestingly, analysis of pertussis toxin sensitivity indicates that there are at least 2 distinct G proteins that couple receptors to phospholipase C. For example, the G protein required for chemotactic peptide receptor signaling in neutrophils is sensitive to pertussis toxin, in contrast to the phosphoinositide signaling G protein in B cells. We have also begun to explore the mechanisms by which mIgM signal transduction can be modulated. Stimulation of protein kinase C with phorbol esters or synthetic DG was found to inhibit mIgM-triggered phosphoinositide breakdown. This regulation probably represents a feedback inhibition that would occur with DG produced by phosphoinositide breakdown. Alternatively, there appear to be other signaling pathways that generate DG33, and they could possibly inhibit phosphoinositide breakdown via protein kinase C. This could be an important locus of regulation during B cell activation. For example, other signals could increase or decrease the potency of this feedback inhibition, and thereby adjust the sensitivity of the B cell to antigen. Alternatively, other agents could stimulate protein kinase C directly, or could stimulate another protein kinase which can do the same thing in this regard, and thereby make the B cell insensitive to antigen by preventing antigen receptor signaling.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Signal transduction via the B cell antigen receptor: involvement of a G protein and regulation of signaling. 255 95

Sarcolemmal membranes were isolated from porcine skeletal muscle by modifications of a LiBr-extraction technique. Latency determinations of acetylcholinesterase, ouabain-sensitive p-nitrophenylphosphatase, [3H]ouabain binding, and (Na+ + K+)-ATPase activities indicated that 65-76% of the membranes were sealed inside-out vesicles. The preparations were enriched in cholesterol and phospholipid, and demonstrated adenylate cyclase activity and both cAMP and cGMP phosphodiesterase activities. An indication of the purity of this fraction was that the Ca2+-ATPase activity (0.13 mumol Pi mg-1 min-1 at 37 degrees C) was 3.8% of that of porcine skeletal muscle sarcoplasmic reticulum preparations. Pertussis toxin specifically catalyzed the ADP-ribosylation of a Mr 41,000 sarcolemmal protein, indicating the presence of the inhibitory guanine nucleotide regulatory protein of adenylate cyclase, Ni. An endogenous ADP-ribosyltransferase activity, with several membrane protein substrates, was also demonstrated. The addition of exogenous cAMP-dependent protein kinase or calmodulin promoted the phosphorylation of a number of sarcolemmal proteins. The calmodulin-dependent phosphorylation exhibited an approximate K 1/2 for Ca2+ of 0.5 microM, and an approximate K 1/2 for calmodulin of 0.1 microM. 125I-Calmodulin affinity labeling of the sarcolemma, using dithiobis(succinimidyl propionate), demonstrated the presence of Mr 160,000 and 280,000 calmodulin-binding components in these membranes. These results demonstrate that this porcine preparation will be valuable in the study of skeletal muscle sarcolemmal ion transport, protein and hormonal receptors, and protein kinase-catalyzed phosphorylation.
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PMID:Components of purified sarcolemma from porcine skeletal muscle. 299 26

The structural components involved in transduction of extracellular signals as diverse as a photon of light impinging on the retina or a hormone molecule impinging on a cell have been highly conserved. These components include a recognition unit or receptor (for example, the beta-adrenergic receptor (beta AR) for catecholamines or the 'light receptor' rhodopsin), a guanine nucleotide regulatory or transducing protein, and an effector enzyme (for example, adenylate cyclase or cyclic GMP phosphodiesterase). Molecular cloning has revealed that the beta AR shares significant sequence and three-dimensional homology with rhodopsin. The function of the beta AR is diminished by exposure to stimulatory agonists, leading to desensitization. Similarly, 'light adaptation' involves decreased coupling of photoactivated rhodopsin to cGMP phosphodiesterase activation. Both forms of desensitization involve receptor phosphorylation. The latter is mediated by a unique protein kinase, rhodopsin kinase, which phosphorylates only the light-bleached form of rhodopsin. An analogous enzyme (termed beta AR kinase or beta ARK) phosphorylates only the agonist-occupied beta AR. We report here that beta ARK is also capable of phosphorylating rhodopsin in a totally light-dependent fashion. Moreover, rhodopsin kinase can phosphorylate the agonist-occupied beta AR. Thus the mechanisms which regulate the function of these disparate signalling systems also appear to be similar.
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PMID:Light-dependent phosphorylation of rhodopsin by beta-adrenergic receptor kinase. 301 40

Activities of cyclic-nucleotide-hydrolysing enzymes cAMP-, cCMP- and cGMP phosphodiesterase, the intracellular concentrations of cAMP, cCMP, and cGMP, and the activity of the cAMP-dependent protein kinase were studied in serum-starved 3T3 cells stimulated to proliferate by serum. Within 1 and 2 min after stimulation the activities of cAMP- and cGMP phosphodiesterase were unaffected while the concentration of cGMP was raised and that of cAMP lowered, suggesting increased synthesis of cGMP and simultaneously reduced synthesis of cAMP. 48 h after stimulation, when the cells multiplied rapidly, both the cAMP phosphodiesterase and the cCMP phosphodiesterase were reduced. Evidence was also obtained that cAMP-dependent protein kinase is important for expressing the cAMP effect in the 3T3 cells.
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PMID:Changes in cyclic nucleotide levels and phosphodiesterase and protein kinase activities in mitogenically stimulated 3T3 fibroblasts. 611 70

Eight-position substituted cAMP and cGMP derivatives, and phosphodiesterase inhibitors, modify endogenous 'bursting' activity in Aplysia neuron R15. Several different patterns of activity were elicited depending on the agent used. 8-Benzylthio-cAMP or 8-parachlorophenylthio-cAMP, at concentrations between 5 muM and 0.3 mM, markedly enhanced the depth and duration of the interburst hyperpolarization, and in some cells bursting was inhibited completely. In contrast, 8-parachlorophenyl-thio-cGMP treatment led to some depolarization and to the appearance of long slow bursts, with little effect on the interburst phase. When the parachlorophenylthio-derivatives of cAMP and cGMP were added together at equal concentrations, a pattern consisting of long bursts interrupted by long and deep interburst hyperpolarizations was observed. This pattern could also be elicited by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). IBMX inhibited cAMP and cGMP phosphodiesterases and caused both cAMP and cGMP to accumulate in intact ganglia and in individual identified neuronal cell bodies including that of R15. Another phosphodiesterase inhibitor, Ro 7-2956, was a more potent inhibitor of cAMP than of cGMP phosphodiesterase; Ro 7-2956 also modified bursting activity, and seemed to enhance preferentially the interburst hyperpolarization. At high concentrations the 8-substituted cAMP and cGMP derivatives also inhibited cAMP and cGMP phosphodiesterases. The 8-parachlorophenylthio-derivatives of cAMP and cGMP were indistinguishable from each other in this assay, and thus phosphodiesterase inhibition cannot be responsible for their differential effects on bursting activity. The derivatives stimulated protein kinase activity in Aplysia ganglion homogenates, as measured by the incorporation of 32P from ATP into histone. IBMX and Ro 7-2956 had no detectable effect on protein kinase activity. The concentrations of cAMP and cGMP derivatives required for protein kinase activation (10(-8)M-10(-6)M) were much lower than those required for phosphodiesterase inhibition (10(-5)M-10(-3)M). Thus, differential protein phosphorylation is more likely to be responsible for the effects of cAMP and cGMP derivatives on neuron R15 bursting activity than is differential phosphodiesterase inhibition.
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PMID:Different effects of cAMP and cGMP derivatives on the activity of an identified neuron: biochemical and electrophysiological analysis. 615 97


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