Rate-dependent abbreviation of Ca2+ transient in rat heart is independent of phospholamban phosphorylation

Hussain, Munir; Drago, Guido A.; Colyer, John; Orchard, Clive H.

doi:10.1152/ajpheart.1997.273.2.h695

Cited by 31 publications

(42 citation statements)

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“…Both relaxation and [Ca 2+ ] i decline rates are accelerated at higher frequency in all species studied and enhanced rate of SR Ca 2+ uptake appears to drive both effects [9][10][11][12]. Some reports have shown that FDAR can be strongly suppressed by CaMKII inhibitors (KN-93, KN-62, AIP) [9,[12][13][14], while other reports could not detect effects on FDAR of organic inhibitors or KN-62 [11,[15][16][17]. CaMKII-dependent PLB phosphorylation seemed a plausible FDAR mediator and some data seemed to support that [14,18].…”

Section: Introductionmentioning

confidence: 93%

“…The contribution of PLB and CaMKII to FDAR remains controversial. CaMKII inhibition has been reported to suppress FDAR in several studies [9,12,13], but other studies did not detect FDAR inhibition with KN-93 or KN-62 [11,[15][16][17]. In isolated myocytes CaMKII dependent phosphorylation of PLB at Thr17 occurs in a frequency dependent manner [14,17].…”

Section: Fdar and Cytosolic Ca 2+ Removalmentioning

confidence: 98%

“…It results from accelerated SR Ca 2+ uptake and does not depend on Ca 2+ removal out of the cell [9,11,17]. The contribution of PLB and CaMKII to FDAR remains controversial.…”

Section: Fdar and Cytosolic Ca 2+ Removalmentioning

confidence: 99%

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CaMKII inhibition targeted to the sarcoplasmic reticulum inhibits frequency-dependent acceleration of relaxation and Ca2+ current facilitation

Picht

DeSantiago

Huke

et al. 2007

Journal of Molecular and Cellular Cardiology

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Cardiac Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) in heart has been implicated in Ca 2+ current (I Ca ) facilitation, enhanced sarcoplasmic reticulum (SR) Ca2+ release and frequency dependent acceleration of relaxation (FDAR) via enhanced SR Ca 2+ uptake. However, questions remain about how CaMKII may work in these three processes. Here we tested the role of CaM-KII in these processes using transgenic mice (SR-AIP) that express four concatenated repeats of the CaMKII inhibitory peptide AIP selectively in the SR membrane. Wild type mice (WT) and mice expressing AIP exclusively in the nucleus (NLS-AIP) served as controls. Increasing stimulation frequency produced typical FDAR in WT and NLS-AIP, but FDAR was markedly inhibited in SR-AIP. Quantitative analysis of cytosolic Ca 2+ removal during [Ca 2+ ] i decline revealed that FDAR is due to an increased apparent V max of SERCA. CaMKII dependent RyR phosphorylation at Ser2815 and SR Ca 2+ leak were both decreased in SR-AIP vs. WT. This decrease in SR Ca 2+ leak may partly balance the reduced SERCA activity leading to relatively unaltered SR-Ca 2+ load in SR-AIP vs. WT myocytes. Surprisingly, CaMKII regulation of the L-type Ca 2+ channel (I Ca facilitation and recovery from inactivation) was abolished by the SR-targeted CaM-KII inhibition in SR-AIP mice. Inhibition of CaMKII effects on I Ca and RyR function by the SR-localized AIP places physical constraints on the localization of these proteins at the junctional microdomain. Thus SR-targeted CaMKII inhibition can directly inhibit the activation of SR Ca 2+ uptake, SR Ca 2+ release and I Ca by CaMKII, effects which have all been implicated in triggered arrhythmias.

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Section: Introductionmentioning

confidence: 93%

Section: Fdar and Cytosolic Ca 2+ Removalmentioning

confidence: 98%

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CaMKII inhibition targeted to the sarcoplasmic reticulum inhibits frequency-dependent acceleration of relaxation and Ca2+ current facilitation

Picht

DeSantiago

Huke

et al. 2007

Journal of Molecular and Cellular Cardiology

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“…Studies from Bassani et al [36] and De Santiago and coworkers [17] indicated that FDAR is dependent on CaMKII activation, and studies in isolated myocytes suggested that phosphorylation of the Thr 17 residue of PLN is responsible for FDAR [15]. However there are other studies that failed to show either an FDAR dependence on CaMKII activation [2,37,38] or a significant increase in PLB phosphorylation [16,37]. The role of CaMKII in FDAR was investigated using isolated trabeculae and/or myocytes from PLB-KO mouse and rat hearts [17,39].…”

Section: Frequency Dependent Acceleration Of Relaxationmentioning

confidence: 99%

Determinants of frequency-dependent contraction and relaxation of mammalian myocardium

Janssen

Periasamy

2007

Journal of Molecular and Cellular Cardiology

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“…However, opposite results have been observed in studies using isolated rat cardiomyocytes. In an earlier study (36), no significant changes in phosphorylation levels of Ser 16 and/or Thr 17 sites of PLB were obtained with increasing stimulation frequency, whereas Thr 17 phosphorylation was recently reported to increase in a frequency-dependent manner, and the increases in Thr 17 phosphorylation were correlated with enhanced rates of myocyte contraction and relaxation in rat ventricular myocytes (37). In perfused rat hearts, phosphorylation of Thr 17 occurred upon inhibition of protein phosphatase-1 in the presence of elevated extracellular Ca 2ϩ or under acidic conditions (24,25,38), suggesting the possible involvement of Thr 17 phosphorylation under pathophysiological conditions.…”

mentioning

confidence: 91%

A Single Site (Ser16) Phosphorylation in Phospholamban Is Sufficient in Mediating Its Maximal Cardiac Responses to β-Agonists

Chu

Lester

Young

et al. 2000

Journal of Biological Chemistry

143

117

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Phospholamban (PLB) can be phosphorylated at Ser 16by cyclic AMP-dependent protein kinase and at Thr 17 by Ca 2؉ -calmodulin-dependent protein kinase during ␤-agonist stimulation. A previous study indicated that mutation of S16A in PLB resulted in lack of Thr 17 phosphorylation and attenuation of the ␤-agonist stimulatory effects in perfused mouse hearts. To further delineate the functional interplay between dual-site PLB phosphorylation, we generated transgenic mice expressing the T17A mutant PLB in the cardiac compartment of the null background. Lines expressing similar levels of T17A mutant, S16A mutant, or wild-type PLB in the null background were characterized in parallel. Phospholamban (PLB)1 is a low molecular weight phosphoprotein in cardiac sarcoplasmic reticulum (SR). Dephosphorylated PLB is an inhibitor of the affinity of SERCA2 for Ca 2ϩ , and phosphorylation of PLB during ␤-adrenergic stimulation relieves its inhibitory effects on SERCA2 (1, 2). The physiological importance of PLB has been elucidated through the generation of genetically engineered mouse models with alterations in cardiac PLB expression levels (3, 4). Ablation of PLB was associated with significantly enhanced Ca 2ϩ affinity of SERCA2 and myocardial performance (3, 5, 6). The elevated basal contractile parameters could be minimally stimulated by ␤-agonists (3, 7), whereas there were no alterations in the ␤-receptor signaling pathway or the phosphorylation states of other major cardiac phosphoproteins (8). On the other hand, overexpression of PLB was associated with significant depression of contractile parameters, which could be reversed upon phosphorylation of PLB during ␤-agonist stimulation (4). These results indicate that PLB is a key regulator of cardiac function and a prominent mediator of the ␤-adrenergic effects in the myocardium.In vitro studies have shown that PLB can be phosphorylated on Ser 10 by protein kinase C, Ser 16 by cAMP-dependent protein kinase (PKA), and Thr 17 by Ca 2ϩ -calmodulin-dependent protein kinase (CaMKII) (1, 9, 10). Each phosphorylation is associated with stimulation of the apparent affinity of SERCA2 for Ca 2ϩ . In vivo studies have shown that only Ser 16 and Thr 17 are phosphorylated in cardiac myocytes or perfused hearts (11, 12), whereas phosphorylation of PLB by protein kinase C has not been detected in vivo. Phosphorylation of PLB by PKA and CaMKII occurs during ␤-agonist exposure, although the relative contribution of each phosphorylation to the cardiac stimulatory effects is not presently clear. Each phosphorylation appears to occur independently of the other (13-16). Some studies have reported additive effects of PKA and CaMKII phosphorylation of PLB on SR Ca 2ϩ transport (13,14,17,18), whereas others (16, 19) have proposed that maximal stimulation of the Ca 2ϩ pump occurs by phosphorylation at a single site, and additional phosphorylation of the other site does not further stimulate the pump activity.Several in vivo studies have shown that Ser 16 phosphorylation or dephosphorylation precede...

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Rate-dependent abbreviation of Ca2+ transient in rat heart is independent of phospholamban phosphorylation

Cited by 31 publications

References 0 publications

CaMKII inhibition targeted to the sarcoplasmic reticulum inhibits frequency-dependent acceleration of relaxation and Ca2+ current facilitation

CaMKII inhibition targeted to the sarcoplasmic reticulum inhibits frequency-dependent acceleration of relaxation and Ca2+ current facilitation

Determinants of frequency-dependent contraction and relaxation of mammalian myocardium

A Single Site (Ser16) Phosphorylation in Phospholamban Is Sufficient in Mediating Its Maximal Cardiac Responses to β-Agonists

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