scholarly journals Ca 2+ -Calmodulin–Dependent Protein Kinase Phosphorylation of Ryanodine Receptor May Contribute to the β-Adrenergic Regulation of Myocardial Contractility Independently of Increases in Heart Rate

2008 ◽  
Vol 103 (1) ◽  
Author(s):  
Alicia Mattiazzi ◽  
Leticia Vittone ◽  
Cecilia Mundiña-Weilenmann
Keyword(s):  
Heart Rate ◽  
Protein Kinase ◽  
Ryanodine Receptor ◽  
Myocardial Contractility ◽  
Dependent Protein Kinase ◽  
Adrenergic Regulation ◽  
Dependent Protein ◽  
Kinase Phosphorylation

ADR1c mutations enhance the ability of ADR1 to activate transcription by a mechanism that is independent of effects on cyclic AMP-dependent protein kinase phosphorylation of Ser-230

1992 ◽  
Vol 12 (4) ◽  
pp. 1507-1514
Author(s):  
C L Denis ◽  
S C Fontaine ◽  
D Chase ◽  
B E Kemp ◽  
L T Bemis
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Transcriptional Activation ◽  
Growth Conditions ◽  
Dependent Protein Kinase ◽  
Inactive Form ◽  
Dependent Protein ◽  
Kinase Phosphorylation

Four ADR1c mutations that occur close to Ser-230 of the Saccharomyces cerevisiae transcriptional activator ADR1 and which greatly enhance the ability of ADR1 to activate ADH2 expression under glucose-repressed conditions have been shown to reduce or eliminate cyclic AMP-dependent protein kinase (cAPK) phosphorylation of Ser-230 in vitro. In addition, unregulated cAPK expression in vivo blocks ADH2 depression in an ADR1-dependent fashion in which ADR1c mutations display decreased sensitivity to unregulated cAPK activity. Taken together, these data have suggested that ADR1c mutations enhance ADR1 activity by blocking cAPK phosphorylation and inactivation of Ser-230. We have isolated and characterized an additional 17 ADR1c mutations, defining 10 different amino acid changes, that were located in the region defined by amino acids 227 through 239 of ADR1. Three observations, however, indicate that the ADR1c phenotype is not simply equivalent to a lack of cAPK phosphorylation. First, only some of these newly isolated ADR1c mutations affected the ability of yeast cAPK to phosphorylate corresponding synthetic peptides modeled on the 222 to 234 region of ADR1 in vitro. Second, we observed that strains lacking cAPK activity did not display enhanced ADH2 expression under glucose growth conditions. Third, when Ser-230 was mutated to a nonphosphorylatable residue, lack of cAPK activity led to a substantial increase in ADH2 expression under glucose-repressed conditions. Thus, while cAPK controls ADH2 expression and ADR1 is required for this control, cAPK acts by a mechanism that is independent of effects on ADR1 Ser-230. It was also observed that deletion of the ADR1c region resulted in an ADR1c phenotype. The ADR1c region is, therefore, involved in maintaining ADR1 in an inactive form. ADR1c mutations may block the binding of a repressor to ADR1 or alter the structure of ADR1 so that transcriptional activation regions become unmasked.

scholarly journals Ca2+/calmodulin-dependent kinase II-dependent regulation of atrial myocyte late Na+ current, Ca2+ cycling, and excitability: a mathematical modeling study

2017 ◽  
Vol 313 (6) ◽  
pp. H1227-H1239 ◽  
Author(s):  
Birce Onal ◽  
Daniel Gratz ◽  
Thomas J. Hund
Keyword(s):  
Protein Kinase ◽  
Computational Model ◽  
Ryanodine Receptor ◽  
The United States ◽  
Atrial Myocytes ◽  
Open Probability ◽  
Dependent Protein Kinase ◽  
Protein Kinase Ii ◽  
Dependent Protein ◽  
Atrial Myocyte

Atrial fibrillation (AF) affects more than three million people per year in the United States and is associated with high morbidity and mortality. Both electrical and structural remodeling contribute to AF, but the molecular pathways underlying AF pathogenesis are not well understood. Recently, a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the regulation of persistent “late” Na+ current ( INa,L) has been identified. Although INa,L inhibition is emerging as a potential antiarrhythmic strategy in patients with AF, little is known about the mechanism linking INa,L to atrial arrhythmogenesis. A computational approach was used to test the hypothesis that increased CaMKII-activated INa,L in atrial myocytes disrupts Ca2+ homeostasis, promoting arrhythmogenic afterdepolarizations. Dynamic CaMKII activity and regulation of multiple downstream targets [ INa,L, L-type Ca2+ current, phospholamban, and the ryanodine receptor sarcoplasmic reticulum Ca2+-release channel (RyR2)] were incorporated into an existing well-validated computational model of the human atrial action potential. Model simulations showed that constitutive CaMKII-dependent phosphorylation of Nav1.5 and the subsequent increase in INa,L effectively disrupt intracellular atrial myocyte ion homeostasis and CaMKII signaling. Specifically, increased INa,L promotes intracellular Ca2+ overload via forward-mode Na+/Ca2+ exchange activity, which greatly increases RyR2 open probability beyond that observed for CaMKII-dependent phosphorylation of RyR2 alone. Increased INa,L promotes atrial myocyte repolarization defects (afterdepolarizations and alternans) in the setting of acute β-adrenergic stimulation. We anticipate that our modeling efforts will help identify new mechanisms for atrial NaV1.5 regulation with direct relevance for human AF. NEW & NOTEWORTHY Here, we present a novel computational model to study the effects of late Na+ current ( INa,L) in human atrial myocytes. Simulations predict that INa,L promotes intracellular accumulation of Ca2+, with subsequent dysregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling and ryanodine receptor 2-mediated Ca2+ release. Although INa,L plays a small role in regulating atrial myocyte excitability at baseline, CaMKII-dependent enhancement of the current promoted arrhythmogenic dynamics. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/camkii-dependent-regulation-of-atrial-late-sodium-current-and-excitability/ .

Relaxin stimulates atrial natriuretic peptide secretion in perfused rat heart

1996 ◽  
Vol 150 (3) ◽  
pp. 487-495 ◽  
Author(s):  
M Toth ◽  
P Taskinen ◽  
H Ruskoaho
Keyword(s):  
Heart Rate ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Rat Heart ◽  
Perfusion Pressure ◽  
Kinase Inhibitor ◽  
Dependent Protein Kinase ◽  
Kinase C ◽  
Dependent Protein ◽  
Heart Preparation

Abstract Relaxin, a reproductive hormone of the insulin-like growth factor family, increases heart rate in experimental animals but its other actions on cardiac function and cellular mechanisms responsible for the positive chronotrophic effect remain unknown. We have studied the actions of human recombinant gene-2 relaxin on the release of atrial natriuretic peptide (ANP) and cardiac function (heart rate, contractile force, perfusion pressure) as well as the underlying signal transduction mechanisms by using the isolated perfused spontaneously beating rat heart preparation. The administration of relaxin into the perfusion fluid at concentrations of 1·5, 3 or 10 nm for 30 min caused a dose-dependent sustained increase in heart rate, while contractile force and perfusion pressure remained unchanged. In addition, infusion of relaxin at a concentration of 10 nm into the perfusate produced a gradual 1·5-fold increase in immunoreactive ANP (IR-ANP) secretion (from 456 ± 76 to 701 ± 124 pg/ml, F=4·5, P<0·001). The ANP secretory and chronotrophic effects of relaxin appear to involve the activation of protein kinase C, since administration of a protein kinase C inhibitor staurosporine at a concentration of 30 nm completely blocked the effect of relaxin (10 nm) on IR-ANP secretion P<0·001) and heart rate (P<0·001). A cAMP-dependent protein kinase inhibitor, H-89 (100 nm), also substantially reduced the ANP secretory effect of relaxin and attenuated the increase in heart rate during the sustained phase of the relaxin infusion (P<0·001). KN-62 (3 μm), a Ca2+/calmodulin-dependent protein kinase inhibitor, decreased the positive chronotrophic effect of relaxin (P<0·001) but did not influence significantly the effect of relaxin on IR-ANP release in isolated perfused rat heart preparation. These results provide the first evidence that relaxin stimulates the secretion of ANP from isolated perfused rat hearts. Our results also suggest that relaxin modulates ANP secretion by activation of protein kinase C and cAMP-dependent protein kinase pathways. Journal of Endocrinology (1996) 150, 487–495

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