Uptake of Calcium by the Sarcoplasmic Reticulum and Its Regulation and Functional Consequences

1984 ◽  
pp. 255-277
Author(s):  
Michihiko Tada ◽  
Munekazu Shigekawa ◽  
Yasuharu Nimura
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Functional Consequences

scholarly journals Loss of CASK Accelerates Heart Failure Development

2021 ◽  
Vol 128 (8) ◽  
pp. 1139-1155
Author(s):  
Julian Mustroph ◽  
Can M. Sag ◽  
Felix Bähr ◽  
Anna-Lena Schmidtmann ◽  
Shamindra N. Gupta ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Ventricular Arrhythmias ◽  
Contractile Function ◽  
Aortic Constriction ◽  
Functional Consequences ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Human And Mouse ◽  
Increased Susceptibility

Rationale: Increased myocardial activity of CaMKII (Ca/calmodulin-dependent kinase II) leads to heart failure and arrhythmias. In Drosophila neurons, interaction of CaMKII with CASK (Ca/CaM-dependent serine protein kinase) has been shown to inhibit CaMKII activity, but the consequences of this regulation for heart failure and ventricular arrhythmias are unknown. Objective: We hypothesize that CASK associates with CaMKII in human and mouse hearts thereby limiting CaMKII activity and that altering CASK expression in mice changes CaMKII activity accordingly, with functional consequences for contractile function and arrhythmias. Methods and Results: Immunoprecipitation revealed that CASK associates with CaMKII in human hearts. CASK expression is unaltered in heart failure but increased in patients with aortic stenosis. In mice, cardiomyocyte-specific knockout of CASK increased CaMKII-autophosphorylation at the stimulatory T287 site, but reduced phosphorylation at the inhibitory T305/306 site. Knockout of CASK mice showed increased CaMKII-dependent sarcoplasmic reticulum Ca leak, reduced sarcoplasmic reticulum Ca content, increased susceptibility to ventricular arrhythmias, greater loss of ejection fraction, and increased mortality after transverse aortic constriction. Intriguingly, stimulation of the cardiac glucagon-like peptide 1 receptor with exenatide increased CASK expression resulting in increased inhibitory CaMKII T305 phosphorylation, reduced CaMKII activity, and reduced sarcoplasmic reticulum Ca leak in wild type but not CASK-KO. Conclusions: CASK associates with CaMKII in the human heart. Knockout of CASK in mice increases CaMKII activity, leading to contractile dysfunction and arrhythmias. Increasing CASK expression reduces CaMKII activity, improves Ca handling and contractile function.

Functional alterations in adult rat myocytes after overexpression of phospholamban with use of adenovirus

1999 ◽  
Vol 1 (2) ◽  
pp. 41-50 ◽  
Author(s):  
KERRY DAVIA ◽  
ROGER J. HAJJAR ◽  
CESARE M. N. TERRACCIANO ◽  
NATASHA SINGH KENT ◽  
HARDEEP K. RANU ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Human Heart ◽  
Ventricular Myocytes ◽  
Adenoviral Vectors ◽  
Functional Changes ◽  
Adult Rat ◽  
Plasmic Reticulum ◽  
Adult Cardiac Myocytes ◽  
Functional Consequences ◽  
Rat Myocytes

Davia, Kerry, Roger J. Hajjar, Cesare M. N. Terracciano, Natasha Singh Kent, Hardeep K. Ranu, Peter O'Gara, Anthony Rosenzweig, and Sian E. Harding. Functional alterations in adult rat myocytes after overexpression of phospholamban with use of adenovirus. Physiol. Genomics 1: 41–50, 1999.—An increased phospholamban (PLB)-to-sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) ratio has been suggested to contribute to the slowing of relaxation in failing human ventricle. We have used an adenoviral vector carrying the sequence for PLB to increase this ratio in isolated adult rat ventricular myocytes, and we have examined the functional consequences. With use of adenoviral vectors, the PLB content of adult rat myocytes was increased 2.73-fold, with SERCA2a levels unchanged. Maximum contraction amplitude of PLB-overexpressing myocytes was decreased to 6.9 ± 0.3% shortening compared with 11.2 ± 0.8% for 24-h controls (Con; P < 0.001, 5 preparations, 103 myocytes). Maximum rates of shortening and relengthening were also significantly decreased. Ca2+ transient amplitudes were slightly depressed, and time to 50% decay of the transients was significantly increased: 237 ± 18 ( n = 14 myocytes) and 432 ± 32 ms in Con and PLB ( n = 15) myocytes, respectively ( P < 0.001). The amount of Ca2+ in the sarcoplasmic reticulum stores was reduced by 21% ( P < 0.05). Relaxation was significantly slower in PLB than in Con myocytes when the Na+/Ca2+ exchanger was blocked but not when sarcoplasmic reticulum Ca2+ uptake was inhibited. Adenovirus infection with Ad.RSV.PLB was therefore able to produce functional changes in adult cardiac myocytes within 24 h, consistent with overexpression of PLB and similar to those seen in failing human heart.

scholarly journals Cardiac ryanodine receptor phosphorylation: target sites and functional consequences

2006 ◽  
Vol 396 (1) ◽  
Author(s):  
Donald M. Bers
Keyword(s):  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Release Channel ◽  
New Information ◽  
Biochemical Journal ◽  
Functional Consequences ◽  
Altered Regulation ◽  
A Site ◽  
Cardiac Ryanodine Receptor

A study by Xiao and co-workers in this issue of the Biochemical Journal demonstrates PKA (protein kinase A)-dependent phosphorylation of Ser-2030 on the cardiac ryanodine receptor (RyR2) that is activated by β-adrenergic agonists. They show that RyR2 phosphorylation at this site is not appreciably altered in heart failure samples, but retains PKA-dependence of phosphorylation. They contrast this with RyR2 phosphorylation at Ser-2808, a site previously reported to be the key and only PKA target site on RyR2. Here Ser-2808 phosphorylation was found to be relatively insensitive to either PKA activation or inhibition. These results add important new information to a highly controversial field. This issue is important because it is increasingly clear that altered regulation of the gating of the RyR2 sarcoplasmic reticulum Ca2+-release channel (e.g. by phosphorylation) is critically important in mediating altered diastolic sarcoplasmic reticulum Ca2+ release. This may contribute to both reduced cardiac function and arrhythmogenesis in humans carrying mutations in the RyR2 gene and with acquired heart failure of varied aetiology. This study brings some new answers, but also raises additional new questions that will require further investigation.

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