Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta adrenergic receptor-mediated relaxation of blood vessels declines with age although the mechanism is unknown. We have utilized the mesenteric artery and aorta of young and older rats to investigate this problem. In vessels from 12-month-old rats there was a marked loss in relaxation mediated by beta adrenergic and adenosine receptors compared to younger rats whereas relaxation induced by muscarinic cholinergic receptors, [cyclic AMP (cAMP) independent], was not impaired. Maximal relaxation to forskolin and dibutyryl cAMP were intact in the vessels from older rats. Isoproterenol-stimulated cAMP accumulation and cAMP-dependent protein kinase activation were attenuated markedly in the vessels from the older rats. Maximal forskolin-stimulated cAMP accumulation and cAMP-dependent protein kinase activation were similar in older and young animals. There was an excellent correlation between cAMP-dependent protein kinase activity and relaxation and the relationship was similar in the two age groups. Continuous infusion of the beta adrenergic antagonist timolol for 1 week into older animals partially restored relaxation to beta adrenergic and adenosine receptor agonists in the aorta. These results suggest that the age-related loss of response to beta adrenergic receptor agonist-induced relaxation may be due in part to attenuated activation of cAMP dependent protein kinase and this change may be partially dependent on endogenous catecholamines.
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PMID:Role of cyclic AMP-dependent protein kinase in the diminished beta adrenergic responsiveness of vascular smooth muscle with increasing age. 254 12

The beta-adrenergic agonist isoproterenol stimulates immunoreactive atrial natriuretic peptide (IR-ANP) secretion by superfused rat atria in vitro. beta-Adrenergic agonists alter the cellular handling of calcium, which culminates in a rise in the systolic calcium concentration. This is achieved by increasing calcium influx through voltage-dependent calcium channels and by increasing the storage pool of calcium in the sarcoplasmic reticulum (SR). We therefore asked the question whether isoproterenol-stimulated IR-ANP secretion was dependent on the protein kinase A-induced rise in systolic calcium or was due to a direct effect of protein kinase A activation. Isolated rat left atria paced at 3 Hz were superfused in vitro. IR-ANP secretion was determined by radioimmunoassay of timed collections of the superfusate. Superfusion with 0.1 microM isoproterenol or 0.5 mM dibutyryl cyclic AMP increased IR-ANP secretion twofold. Stimulated IR-ANP secretion was lowered to near baseline by lowering the buffer calcium concentration from 1.8 to 0.2 mM or by adding to the superfusate 10 microM nitrendipine (a calcium-channel blocker) or 1 microM ryanodine (an inhibitor of SR calcium release). Superfusion of nonbeating, electrically quiescent left atria with 0.1 microM isoproterenol failed to stimulate IR-ANP secretion. We conclude: 1) Isoproterenol-stimulated IR-ANP secretion is dependent on calcium influx through voltage-dependent calcium channels and on the release of calcium from the SR. 2) Enhanced calcium influx alone is not adequate to maintain isoproterenol-stimulated IR-ANP secretion. 3) The SR appears to be the primary source of calcium for isoproterenol-stimulated IR-ANP secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium, its role in isoproterenol-stimulated atrial natriuretic peptide secretion by superfused rat atria. 254 60

A mouse beta 2-adrenergic receptor (beta 2AR) DNA clone was transfected and expressed in a mouse adrenocortical tumor cell line (Kin8) that lacks both beta 2AR and cAMP-dependent protein kinase (PKA). The receptor displayed a characteristic beta 2AR agonist binding profile that was similar to that observed in beta 2AR-transfected PKA+ mouse adrenocortical tumor cells (Y1). Isoproterenol treatment of beta 2AR-transfected Kin8 and Y1 cells resulted in a rapid loss of surface beta 2AR, as determined by the binding of the hydrophilic beta 2AR radioligand [3H]CGP 12177 [( 3H]CGP), followed by a decrease in adenylate cyclase activity. Sequestration of beta 2AR in Kin8 cells was beta 2AR agonist specific, temperature dependent, and rapidly reversible. Repeated treatment and recovery from isoproterenol incubation resulted in a cycling of surface [3H]CGP binding. The reappearance of [3H]CGP binding following short isoproterenol treatment was not affected by cycloheximide treatment of the cells. Prolonged incubation of beta 2AR-transfected Kin8 cells with isoproterenol resulted in the down-regulation of beta 2AR protein without a change in beta 2AR mRNA levels. Polysome profiles of control and down-regulated cells revealed that translation of beta 2AR mRNA is inefficient and does not change upon prolonged agonist treatment. Protein synthesis was required to reverse the down-regulation of beta 2AR. These results indicate that neither sequestration nor down-regulation of beta 2AR depends on PKA.
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PMID:Beta 2-adrenergic receptor regulation after transfection into a cell line deficient in the cAMP-dependent protein kinase. 254 82

Isoprenaline is a beta-adrenergic agonist of clinical importance as a remedy for asthma. In airway smooth muscle its relaxant action is accompanied by hyperpolarization of the membrane and elevation of the level of intracellular cyclic AMP. Hyperpolarization and relaxation are also induced by drugs such as forskolin, theophylline and dibutyryl cAMP, indicating that cAMP-dependent phosphorylation is involved in producing the electrical response. Cyclic AMP-dependent protein kinase (protein kinase A) has been reported to activate Ca2+-dependent K+ channels in cultured aortic smooth muscle cells and snail neurons. The membrane of tracheal smooth-muscle cells is characterized by a dense distribution of Ca2+-dependent K+-channels. We have now examined the effect of isoprenaline and protein kinase A on Ca2+-dependent K+-channels in isolated smooth muscle cells of rabbit trachea, using the patch-clamp technique. Our results show that the open-state probability of Ca2+-dependent K+-channel of tracheal myocytes is reversibly increased by either extracellular application of isoprenaline or intracellar application of protein kinase A. We also show that this effect is significantly enhanced and prolonged in the presence of a potent protein phosphatase inhibitor, okadaic acid.
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PMID:Regulation of Ca2+-dependent K+-channel activity in tracheal myocytes by phosphorylation. 255 Aug 23

We have examined the acute effects of insulin and isoproterenol on the phosphorylation state of the insulin-regulatable glucose transporter (IRGT) in rat adipocytes. The IRGT was immunoprecipitated from either detergent-solubilized whole-cell homogenates or subcellular fractions of 32P-labeled fat cells and subjected to sodium dodecyl sulfate/polyacrylamide gel electrophoresis. The 32P-labeled IRGT was detected by autoradiography as a species of apparent Mr 46,000. Insulin stimulated translocation of the IRGT from low-density microsomes to the plasma membrane but did not affect phosphorylation of the transporter in either fraction. Isoproterenol inhibited insulin-stimulated glucose transport by 40% but was without effect on the subcellular distribution of the transporter in either the presence or absence of insulin. Isoproterenol stimulated phosphorylation of the IRGT 2-fold. Incubating cells with dibutyryl-cAMP and 8-bromo-cAMP also stimulated phosphorylation 2-fold, and the transporter was phosphorylated in vitro when IRGT-enriched vesicles were incubated with cAMP-dependent protein kinase and [gamma-32P]ATP. These results suggest that isoproterenol stimulates phosphorylation of the IRGT via a cAMP-dependent pathway and that phosphorylation of the transporter may modulate its ability to transport glucose.
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PMID:Isoproterenol stimulates phosphorylation of the insulin-regulatable glucose transporter in rat adipocytes. 255 13

Experiments were carried out in single ventricular cells of the guinea-pig heart. Isoproterenol, forskolin, intracellularly applied cyclic AMP and 3-isobutyl-1-methylxanthine increased the delayed rectifier potassium current (IK). The effect of isoproterenol was abolished by intracellularly applied guanosine 5'-O-(3-thio-triphosphate). These results indicate that isoproterenol stimulates beta-adrenoceptors to activate adenylate cyclase by mediation through the stimulatory GTP-binding protein, and causes an increase in intracellular cyclic AMP levels. Then IK is probably increased by phosphorylation of the IK-channel protein by cyclic AMP-dependent protein kinase.
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PMID:Mechanisms of beta-adrenoceptor mediated increase in delayed rectifier potassium current. 256 Dec 34

We isolated cDNAs encoding a 115 kd human atrial natriuretic peptide (alpha ANP) receptor (ANP-A receptor) that possesses guanylate cyclase activity, by low-stringency hybridization with sea urchin Arbacia punctulata membrane guanylate cyclase probes. The human ANP-A receptor has a 32 residue signal sequence followed by a 441 residue extracellular domain homologous to the 60 kd ANP-C receptor. A 21 residue transmembrane domain precedes a 568 residue cytoplasmic domain with homology to the protein kinase family and to a subunit of the soluble guanylate cyclase. COS-7 cells transfected with an ANP-A receptor expression vector displayed specific [125I]alpha ANP binding, and exhibited alpha ANP stimulated cGMP production. These data demonstrate a new paradigm of cellular signal transduction where extracellular ligand binding allosterically regulates cyclic nucleotide second-messenger production by a receptor cytoplasmic catalytic domain.
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PMID:Human atrial natriuretic peptide receptor defines a new paradigm for second messenger signal transduction. 256 67

The regulation of the cytosolic calcium concentration was investigated in freshly isolated adult bovine tracheal smooth muscle cells using fura 2. These cells contain 1.1 and 1.8 pmol of cGMP kinase and cAMP kinase per mg protein, respectively. Carbachol, histamine, serotonin, isoproterenol, and salbutamol increased the cytosolic calcium in a dose-dependent manner from 79 nM to about 650 nM. Preincubation of these cells for 20 min with isoproterenol, forskolin, 8-Br-cAMP and 8-(4-Cl-phenyl)thio-cAMP did not lower carbachol-induced increases in cytosolic calcium concentration, whereas the phorbol ester 12-O-tetradecanoylphorbol 13-acetate, the atrionatriuretic factor, isobutylmethylxanthine, and 8-Br-cGMP lowered cytosolic calcium. The active fragment of cGMP kinase, but not the catalytic subunit of cAMP kinase lowered carbachol-induced calcium levels. Carbachol released calcium from intracellular stores and increased calcium influx from the extracellular space. The influx was inhibited by preincubation with the calcium channel blockers nitrendipine or gallopamil. Both carbachol-stimulated pathways were suppressed by 8-Br-cGMP. Isoproterenol increased only the influx of calcium from the outside by a channel which was blocked by calcium channel blockers or 8-Br-cGMP. Forskolin and 8-Br-cAMP lowered carbachol- and isoproterenol-stimulated increases in calcium when added shortly before or after the addition of the agonist. In addition, isoproterenol decreased carbachol-stimulated calcium levels when added 10 s after carbachol. The calcium stimulatory effect of isoproterenol was abolished by preincubation of the cells with pertussis toxin or cholera toxin. These results show (a) that the beta 2-adrenoceptor couples in isolated tracheal smooth muscle cells to a dihydropyridine- and pertussis toxin-sensitive calcium channel; (b) that the same channel is opened by carbachol; (c) that cGMP kinase is very effective in decreasing elevated cytosolic calcium concentrations, whereas cAMP-dependent protein kinase has a variable effect on stimulated cytosolic calcium levels.
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PMID:Regulation of cytosolic calcium by cAMP and cGMP in freshly isolated smooth muscle cells from bovine trachea. 284 48

The actions of cyclic AMP are subject to several levels of post-receptor modulation in cardiac tissue. Isoproterenol and prostaglandin E1 both stimulate cAMP accumulation, but only isoproterenol causes activation of particulate cAMP-dependent protein kinase, leading to activation of phosphorylase kinase and glycogen phosphorylase, and inhibition of glycogen synthase. Through the use of isolated, adult ventricular myocytes, we have determined that the hormone-specific activation of glycogen phosphorylase is due to subcellular compartmentation of cAMP. There is some evidence that cyclic nucleotide phosphodiesterases, whose activity is stimulated by alpha 1-adrenergic agonists in isolated myocytes, may have a role in compartmentation. Phosphoinositide hydrolysis is stimulated by alpha 1 and muscarinic agonists, presumably leading to activation of protein kinase C, which in turn has multiple effects on hormone-sensitive adenylate cyclase.
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PMID:Post-receptor modulation of the effects of cyclic AMP in isolated cardiac myocytes. 284 10

Reduced inotropic responsiveness by spontaneously hypertensive rats (SHR) to beta agonists is associated with, and may be secondary to, a decline in cardiac membrane-bound beta adrenoceptors. It is widely assumed that this decline reflects a desensitization of the receptor secondary to enhanced sympathetic drive, but direct evidence is lacking. We examined this issue in cell-free cardiac preparations from age-matched SHR and Wistar-Kyoto (WKY) rats. Isoproterenol induced a time- and concentration-dependent decline in membrane-bound beta receptors but was considerably more effective in WKY than in SHR (43% decline versus 29% in SHR, P less than 0.01). Since cyclic AMP-protein kinase inhibitor prevented only 15-20% of the isoproterenol-induced decline, this was probably mediated by the beta receptor kinase. Cyclic AMP-dependent protein kinase induced a 38% desensitization in WKY rats but was completely ineffective in SHR. These results suggest that desensitization of the beta receptor is impaired in SHR, probably because the structural organization of the receptor in the cardiac membranes is altered.
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PMID:Impaired desensitization of cardiac beta-adrenoceptors in the spontaneously hypertensive rat. 285 23


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