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  • protein phosphorylation  (2)
  • G proteins  (1)
  • PDE-isoenzymes  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Protein phosphorylation in isolated trabeculae from nonfailing and failing human hearts (1996)
    Springer
    Molecular and cellular biochemistry 157 (1996), S. 171-179 
    Details
    ISSN: 1573-4919
    Keywords: human heart ; force of contraction ; protein phosphorylation ; phospholamban
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Disturbances in the cAMP production during β-adrenergic stimulation and alterations of Ca 2+ transport controlling proteins and their regulation in the sarcoplasmic reticulum might be involved in the pathogenesis of the failing human heart. Thus, we investigated the cAMP-mediated phosphorylation of phospholamban, troponin I and C-protein in electrically driven, intact isolated trabeculae carneae from nonfailing and failing (NYHA IV) human hearts in parallel to contractile properties on the same tissue samples. The increase in force of contraction induced by isoproterenol (0.2 μM) or pimobendan (100 μM), a phosphodiesterase inhibitor, was diminished in the failing human hearts compared to nonfailing hearts by 49% and 36%, respectively. Concomitantly the isoproterenol-induced phosphorylation (pmol P/mg homogenate protein) of phospholamban, troponin I and C-protein was reduced from 13.0 ± 2.4 (n = 4), 30.5 ± 1.5 (n = 5) and 11.0 ± 1.3 (n = 5) in the nonfailing heart to 5.2 ±0.6 (n = 13), 14.6 ± 2.2 (n = 16) and 7.1 ± 1.0 (n = 6) in the failing human heart, respectively. Pimobendan changed the phosphorylation state of these proteins similar to isoproterenol. The fact that combined addition of both agents or dibuturyl CAMP (1 mM) alone restored the phosphorylation capacity as observed in the control groups indicates that i) a reduced cAMP generation is related to the reduced phosphorylation of regulatory phosphoproteins located in the sarcoplasmic reticulum and contractile apparatus e.g. phospholamban, troponin I and C-protein, that ii) there is a relationship between protein phosphorylation state and contractile activity and that iii) no changes in the respective content of phosphoproteins are involved in the limitation of cAMP-mediated inotopic activity in the failing human heart. (Mol Cell Biochem 157: 171–179, 1996)
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227896
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  • 2
    Electronic Resource
    Electronic Resource
    G proteins, adenylyl cyclase and related phosphoproteins in the developing rat heart (1996)
    Springer
    Molecular and cellular biochemistry 163-164 (1996), S. 31-38 
    Details
    ISSN: 1573-4919
    Keywords: developing heart ; G proteins ; adenylyl cyclase ; phosphoproteins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The postnatal alterations of the composition of a subunit isoforms (Giαc, G iα3 Goα, and Gqα of G proteins, the adenylyl cyclase activity as well as of cAMP-regulated phosphoproteins e.g. troponin and phospholamban were investigated in the ventricular tissue of 1, 7, 30 days old rats. Quantitative immunodetection revealed a 5.7-fold decrease in Giα3 at 30th postnatal day compared with the postnatal day 1 and up to 15-fold at 4 months. The amounts of Gqα and G∞ as well as the Gα subunits were found to be higher in the earlier life period compared to the adult. In contrast, the content of Gsα was uneffected by the developmental state. Basal adenylyl cyclase activity (pmoles cAMP/min × mg protein) increased from 30.9 ± 5.0, 36.8 ± 5.0 to 63.9 ± 5.9 at 1st, 7th and 30th postnatal day, respectively. Isoprenaline (100 μM) enhanced the activity of adenylyl cyclase from day 1, 7–30 from 46.2 ± 7.0, 79.1 ± 9.2 to 120.5 ± 7.2, respectively. The effects of forskolin and NaF on adenylyl cyclase activity was found to be not influenced within the first postnatal month. Furthermore, a developmentally controlled expression of cardiac troponin I was observed (6-fold from the first to the 28th postnatal day) whereas the level of phospholamban was found to be age-independent. In conclusion, there is an increase in the efficiency of the β-adrenergic signal transfer mainly caused by a reduction of the inhibitiory G proteins and a dominance of the Gsα-linked pathway in the postnatal rat heart. Furthermore the developmentally controlled expression of troponin I might be of functional importance in the cAMP-supported relaxation. Additionally, altered Gqα, Goα and Gβ pattern of the developing rat ventricle may play a role in the observed change of α-adrenerg-mediated heart contractility as well as in cardiac differentiation and growth processes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408638
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  • 3
    Electronic Resource
    Electronic Resource
    On the mechanism and possible therapeutic application of delayed adaptation of the heart to stress situations (1995)
    Springer
    Molecular and cellular biochemistry 147 (1995), S. 115-122 
    Details
    ISSN: 1573-4919
    Keywords: cardioprotection ; delayed adaptation ; cAMP ; PDE-isoenzymes ; prolongation of protection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Mild (not harmful) stress may initiate anadaptive mechanism, protecting the heart from harmful consequences of a more severe stress. There are at least three known types of cardiac adaptation to stress such as: a) the gradually developing long lasting adaptation to chronic mechanical overload, leading to cardiac hypertrophy, later to cardiomyopathy and heart failure, b) the rapidly developing adaptation to moderate stress initiated by ‘preconditioning’ brief coronary occlusion(s) or brief periods of rapid cardiac pacing, protecting for less than 1 h against consequences of a subsequent, severe stress, c) the later appearing, more prolonged cardio-protective adaptation, described by us in 1983, induced by various forms of more severe but not injurious stimuli, such as an optimal dose of prostacyclin or its stable analogues; or a series of brief periods of rapid pacings. This form of cardiac adaptation to stress protects for 24–48 h against consequences of a more severe stress such as: 1. myocardial ischaemia; 2. early and late postocclusion and reperfusion arrhythmias; 3. early morphologic changes secondary to ischaemia and reperfusion; 4. ischaemia induced myocadial loss of K+ and accumulation of Na+ and Ca++; 5. it may increase the tolerance to the toxic effects of cardiac glycosides. A reduced response to beta-adrenergic stimuli and a concomitant increase in activity and amount of PDE I and IV was shown by us earlier. The hypothesis that these factors may play a role in the mechanism of delayed protection was confirmed by our present findings according to which 7-oxo-PgI2-treatment greatly attenuated the dose dependent isoprenaline-induced increase in contractility, relaxation and myocardial cAMP level in rat hearts isolated 48h after 7-oxo-PgI2. In addition all these values are in close correlation with each other. The endogenous ‘self-defence’ of the heart based on adaptation represents anew therapeutic concept, different from the classical drug-receptor interaction produced protection. Its possible exploitation to therapeutic use requires that the adaptation inducing stress should beapplicable topatients, furthermore prolongation of duration of protection should be possible. As a first step in testing applicability to therapy we had to show that drug induced adaptive protection is existing in the conscious animal. In our present study we found an attenuation of rapid pacing induced elevation of the ST-segment in the endocardial electrogram and in the left ventricular end diastolic pressure in conscious rabbits 24–48 h after treatment with Iloprost. Besides we found an attenuation of tachycardia and arrhythmias due to two stage coronary artery ligation in conscious dog 48 h after pretreatment with 7-oxo-PgI2. Finally we were able to demonstrate that protection against coronary artery occlusion-induced ST segment elevation and arrhythmias can be prolonged at will by periodically repeated maintenance doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00944791
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  • 4
    Electronic Resource
    Electronic Resource
    β2-Adrenoceptor activation by zinterol causes protein phosphorylation, contractile effects and relaxant effects through a cAMP pathway in human atrium (1996)
    Springer
    Molecular and cellular biochemistry 163-164 (1996), S. 113-123 
    Details
    ISSN: 1573-4919
    Keywords: human atrium ; β2-adrenoceptors ; receptor binding ; zinterol ; adenylyl cyclase stimulation ; atrial relaxation and contraction ; protein phosphorylation ; troponin I ; C-protein ; phospholamban
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Evidence from ventricular preparations of cat, sheep, rat and dog suggests that both β1-adrenoceptors (β1AR) and β2-adrenoceptors (β2AR) mediate positive inotropic effects but that only β1AR do it through activation of a cAMP pathway. On the other hand, our evidence has shown that both β1 AR and β2 AR hasten relaxation of isolated human myocardium consistent with a common cAMP pathway. We have now investigated in the isolated human right atrial appendage, a tissue whose β-AR comprise around 2/3 of β1AR and 1/3 of β2AR, whether or not β2AR-mediated effects occur via activation of a cAMP pathway. We carried out experiments on atria obtained from patients without advanced heart failure undergoing open heart surgery. To activate β2AR, we used the β2AR-selective ligand zinterol. Experiments were carried out on paced atrial strips (1 Hz) and tissue homogenates and membrane particles. Zinterol caused positive inotropic and lusitropic (i.e. reduction of t1:2 of relaxation) effects with EC50 values of 3 and 2 nM, respectively. The zinterol-evoked effects were unaffected by the β AR-selective antagonist CGP 20712A (300 nM) but blocked surmountably by the β2AR-selective antagonist ICI 118551 (50 nM) which reduced both EC50 values to 1 μM. Zinterol stimulated adenylyl cyclase activity with an EC50 of 30 nM and intrinsic activity of 0.75 with respect to (−)-isoprenaline (600 μM); the effects were resistant to blockade by CGP 20712A (300 nM) but antagonised surmountably by ICI 118551 (50 nM). Zinterol bound to membrane PAR labelled with (−)-[125I] cyanopindolol with higher affinity for β2AR than for β- 1 AR; the binding to β2AR but not to β- BAR was reduced by GTPyS (10 μM). In the presence of CGP 20712A (300 nM) (−)-isoprenaline (400 μM); (to activate both β1AR and β2AR maximally) and zinterol (10 μM); increased contractile force 3.4-fold and 2.5-fold respectively and reduced relaxation tut by 32% and 18% respectively. These effects of (−)-isoprenaline and zinterol were associated (5 min incubation) with phosphorylation (pmol P/mg supernatant protein) of troponin I and C-protein to values of 8.4 ± 2.0 vs 12.4 ± 2.3 and 10.1 ± 2.5 vs 8.6 ± 1.6 respectively. (−)-Isoprenaline and zinterol also caused phosphorylation of phospholamban (1.8 ± 0.3 vs 0.4 ± 0.1 pmol P/mg respectively) specifically at serine residues. We conclude that in human atrial myocardium activation of both β1AR and β2AR leads to cAMP-dependent phosphorylation of proteins involved in augmenting both contractility and relaxation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408647
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