scholarly journals Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

2004 ◽  
Vol 279 (50) ◽  
pp. 52095-52105 ◽  
Author(s):  
Francesca Rochais ◽  
Grégoire Vandecasteele ◽  
Florence Lefebvre ◽  
Claire Lugnier ◽  
Hazel Lum ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Negative Feedback ◽  
Adrenergic Stimulation ◽  
Dependent Protein Kinase ◽  
Α Subunit ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Infected Cells ◽  
Camp Levels ◽  
Stimulation Of

Intracardiac cAMP levels are modulated by hormones and neuromediators with specific effects on contractility and metabolism. To understand how the same second messenger conveys different information, mutants of the rat olfactory cyclic nucleotide-gated (CNG) channel α-subunit CNGA2, encoded into adenoviruses, were used to monitor cAMP in adult rat ventricular myocytes. CNGA2 was not found in native myocytes but was strongly expressed in infected cells. In whole cell patch-clamp experiments, the forskolin analogue L-858051 (L-85) elicited a non-selective, Mg2+-sensitive current observed only in infected cells, which was thus identified as the CNG current (ICNG). The β-adrenergic agonist isoprenaline (ISO) also activatedICNG, although the maximal efficiency was ≈5 times lower than with L-85. However, ISO and L-85 exerted a similar maximal increase of the L-type Ca2+current. The use of a CNGA2 mutant with a higher sensitivity for cAMP indicated that this difference is caused by the activation of a localized fraction of CNG channels by ISO. cAMP-dependent protein kinase (PKA) blockade with H89 or PKI, or phosphodiesterase (PDE) inhibition with IBMX, dramatically potentiated ISO- and L-85-stimulatedICNG. A similar potentiation of β-adrenergic stimulation occurred when PDE4 was blocked, whereas PDE3 inhibition had a smaller effect (by 2-fold). ISO and L-85 increased total PDE3 and PDE4 activities in cardiomyocytes, although this effect was insensitive to H89. However, in the presence of IBMX, H89 had no effect on ISO stimulation ofICNG. This study demonstrates that subsarcolemmal cAMP levels are dynamically regulated by a negative feedback involving PKA stimulation of subsarcolemmal cAMP-PDE.

scholarly journals Genetic Involvement of a cAMP-Dependent Protein Kinase in a G Protein Signaling Pathway Regulating Morphological and Chemical Transitions in Aspergillus nidulans

Genetics ◽  
2001 ◽  
Vol 157 (2) ◽  
pp. 591-600
Author(s):  
Kiminori Shimizu ◽  
Nancy P Keller
Keyword(s):  
Protein Kinase ◽  
Aspergillus Nidulans ◽  
Signaling Pathway ◽  
G Protein ◽  
Radial Growth ◽  
Morphological Development ◽  
Dependent Protein Kinase ◽  
Α Subunit ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein

Abstract In the filamentous fungus Aspergillus nidulans, a heterotrimeric G protein α-subunit and an RGS domain protein, encoded by fadA and flbA, respectively, regulate production of the carcinogenic metabolite sterigmatocystin (ST) and asexual spores (i.e., conidia). We investigated the genetic involvement of the cAMP-dependent protein kinase catalytic subunit (PkaA), a potential downstream target of FadA activity, in ST production and conidiation. Relative to wild type, sporulation was decreased in the pkaA overexpression strain but was not totally absent, as occurs in ΔflbA or fadAG42R (fadA-dominant active) strains. Deletion of pkaA resulted in a hyper-conidiating strain with limited radial growth. This phenotype was epistatic to mutation in flbA or fadA; the double mutants ΔpkaA; ΔflbA and ΔpkaA; fadAG42R recovered sporulation and their radial growth was severely restricted. PkaA overexpression also negatively regulated AflR, the ST biosynthesis-specific transcription factor, both transcriptionally and post-transcriptionally. Deletion of pkaA restored ST production in the ΔflbA background but not in the fadAG42R background. These data provide genetic evidence that the FlbA/FadA signaling pathway regulating ST production and morphological development is partially mediated through PkaA.

Relaxing effect of pharmacologic interventions increasing cAMP in rat heart

1981 ◽  
Vol 240 (4) ◽  
pp. H441-H447
Author(s):  
L. Vittone ◽  
A. Grassi ◽  
L. Chiappe ◽  
M. Argel ◽  
H. E. Cingolani
Keyword(s):  
Protein Kinase ◽  
Rat Heart ◽  
Kinase Activity ◽  
Isolated Rat Heart ◽  
Protein Kinase Activity ◽  
Dependent Protein Kinase ◽  
Camp Dependent Protein Kinase ◽  
High Calcium ◽  
Dependent Protein ◽  
Camp Levels

The relationship between cAMP and relaxation was studied in the isolated rat heart beating at constant rate and perfused at constant coronary flow. After treatment during 1 min with different positive inotropic interventions, cyclic nucleotide levels (cAMP and cGMP) and cAMP-dependent protein kinase activity were determined in heart homogenates. Glucagon, norepinephrine, and isoproterenol increased cAMP from 0.503 +/- 0.025 pmol/mg wet wt to 1.051 +/- 0.099, 0.900 +/- 0.064, and 0.982 +/- 0.138, respectively. Simultaneously glucagon, norepinephrine, and isoproterenol increased cAMP-dependent protein kinase activity ratio from 0.21 +/- 0.02 to 0.45 +/- 0.04, 0.33 +/- 0.02, and 0.34 +/- 0.02, respectively. The ratio between maximal velocities of contraction and relaxation (+T/-T) was significantly decreased by these interventions, whereas time to peak tension (TTP) was shortened by norepinephrine and isoproterenol. High calcium, ouabain, and paired stimulation did not affect cAMP levels, TTP, or +T/-T. A striking correlation was found between cAMP-dependent protein kinase activity and relaxation induces, i.e., TTP, -T, or +T/-T (r = +/- 0.7 to -0.9). Results suggest that inotropic interventions increasing cAMP levels might be primarily affecting intracellular mechanisms causing relaxation.

scholarly journals A CaMKII/PDE4D negative feedback regulates cAMP signaling

2015 ◽  
Vol 112 (7) ◽  
pp. 2023-2028 ◽  
Author(s):  
Delphine Mika ◽  
Wito Richter ◽  
Marco Conti
Keyword(s):  
Protein Kinase ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Dependent Protein Kinase ◽  
Protein Targets ◽  
Cardiac Pathophysiology ◽  
Functional Consequences ◽  
Dependent Protein ◽  
Cardiac Excitation ◽  
Camp Levels

cAMP production and protein kinase A (PKA) are the most widely studied steps in β-adrenergic receptor (βAR) signaling in the heart; however, the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is also activated in response to βAR stimulation and is involved in the regulation of cardiac excitation-contraction coupling. Its activity and expression are increased during cardiac hypertrophy, in heart failure, and under conditions that promote arrhythmias both in animal models and in the human heart, underscoring the clinical relevance of CaMKII in cardiac pathophysiology. Both CaMKII and PKA phosphorylate a number of protein targets critical for Ca2+ handling and contraction with similar, but not always identical, functional consequences. How these two pathways communicate with each other remains incompletely understood, however. To maintain homeostasis, cyclic nucleotide levels are regulated by phosphodiesterases (PDEs), with PDE4s predominantly responsible for cAMP degradation in the rodent heart. Here we have reassessed the interaction between cAMP/PKA and Ca2+/CaMKII signaling. We demonstrate that CaMKII activity constrains basal and βAR-activated cAMP levels. Moreover, we show that these effects are mediated, at least in part, by CaMKII regulation of PDE4D. This regulation establishes a negative feedback loop necessary to maintain cAMP/CaMKII homeostasis, revealing a previously unidentified function for PDE4D as a critical integrator of cAMP/PKA and Ca2+/CaMKII signaling.

Effects of isoproterenol on cylic-AMP metabolism in rat ventral prostate

1976 ◽  
Vol 54 (3) ◽  
pp. 327-335 ◽  
Author(s):  
B. K. Tsang ◽  
R. L. Singhal
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Kinase Activity ◽  
Activity Ratio ◽  
Ventral Prostate ◽  
Adrenergic Stimulation ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Stimulation Of

β-Adrenergic stimulation of the ventral prostate cyclic-AMP system was investigated by examining the influence of isoproterenol on endogenous cyclic-AMP levels as well as on the activities of adenylate cyclase (EC 4.6.1.1) and cyclic-AMP-dependent and independent protein kinases (EC 2.7.1.37). Administration of isoproterenol (1 mg/kg, ip) resulted in rapid elevation of adenylate cyclase activity (119%) and cyclic-AMP levels (593%). The observed isoproterenol-stimulated changes in cyclic-AMP metabolism of the ventral prostate were time-dependent and maximal stimulation was seen 5 min after treatment with this β-adrenergic agonist. The increases in prostatic adenylate cyclase and cyclic-AMP also were related to the dose of isoproterenol administered and maximal enhancement of these parameters was seen with 1 mg/kg dose of the agonist. Whereas pretreatment of rats with propranolol (3 mg/kg, ip) partially reversed these alterations, administration of an α-adrenergic antagonist, phentolamine, even at a dose of 5 mg/kg, failed to elicit any appreciable effect. Stimulation of prostatic soluble protein kinase by isoproterenol was associated with a decrease (33%) in the activity of the cyclic-AMP-dependent protein kinase with a concomitant increase (25%) in that of the independent enzyme. Whereas the ability of the enzyme to bind cyclic-[3H] AMP in vitro was decreased (54%) following isoproterenol treatment, the protein kinase activity ratio (−cyclic-AMP/+cyclic-AMP) was significantly elevated from 0.51 ± 0.05 to 0.95 ± 0.08. Although propranolol alone had little or no effect on these parameters, it inhibited partially the isoproterenol-induced alterations in cyclic-AMP-dependent protein kinase and the cyclic-AMP binding capacity. Treatment with propranolol also blocked the increases in the kinase activity ratio and in the activity of cyclic-AMP-independent enzyme seen with isoproterenol. Data suggest that the concentration of ventral prostate cyclic-AMP as well as the activities of adenylate cyclase and cyclic-AMP-dependent and independent form of protein kinases are subject to modulation by β-adrenergic stimulation.

NO releases bombesin-like immunoreactivity from enteric synaptosomes by cross-activation of protein kinase A

1999 ◽  
Vol 276 (6) ◽  
pp. G1521-G1530 ◽  
Author(s):  
M. Kurjak ◽  
R. Fritsch ◽  
D. Saur ◽  
V. Schusdziarra ◽  
H. D. Allescher
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Dependent Protein Kinase ◽  
No Donor ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Camp Levels ◽  
No Releases ◽  
Kinase A

The effect of nitric oxide (NO) on the release of bombesin-like immunoreactivity (BLI) was examined in synaptosomes of rat small intestine. The NO donor S-nitroso- N-acetylpenicillamine (SNAP; 10−7 to 10−4 M) significantly stimulated BLI release. In the presence of the NO scavenger oxyhemoglobin (10−3 M) or the guanylate cyclase inhibitor ODQ (10−5 M), SNAP-induced BLI release was antagonized. In addition, SNAP increased the synaptosomal cGMP content and elevation of cGMP levels by zaprinast (3 × 10−5 M), an inhibitor of the cGMP-specific phosphodiesterase (PDE) type 5, and increased basal and SNAP-induced BLI release. NO-induced BLI release was blocked by Rp-adenosine 3′,5′-cyclic monophosphorothioate (3 × 10−5 M and 10−4 M), an inhibitor of the cAMP-dependent protein kinase A, whereas KT-5823 (3 × 10−6 M) and Rp-8-(4-chlorophenylthio)-cGMP (5 × 10−5M), inhibitors of the cGMP-dependent protein kinase G, had no effect. Because cGMP inhibits the cAMP-specific PDE3, thereby increasing cAMP levels, the role of PDE3 was investigated. Trequinsin (10−8 M), a specific blocker of PDE3, stimulated basal BLI release but had no additive effect on NO-induced release, suggesting a similar mechanism of action. These data demonstrate that because of a cross-activation of cAMP-dependent protein kinase A by endogenous cGMP BLI can be released by NO from enteric synaptosomes.

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