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

Chu, Guoxiang; Lester, James W.; Young, Karen B.; Luo, Wusheng; Zhai, Jing; Kranias, Evangelia G.

doi:10.1074/jbc.m004079200

Cited by 144 publications

(129 citation statements)

References 41 publications

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“…Phosphorylation at both sites, Ser 16 and Thr 17 , relieves the inhibitory effect of PLB on SERCA and enhances SR Ca 2ϩ uptake, although the exact contribution of each phosphorylation site and its specific effect on heart function is not clear (3,6,9). Interestingly, in SERCA2 (ϩ/Ϫ) mice we found an increase in the phosphorylation status of PLB.…”

Section: Discussionmentioning

confidence: 54%

Altered dose response to β-agonists in SERCA1a-expressing hearts ex vivo and in vivo

Huke

Prasad

Nieman

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Altered dose response to ␤-agonists in SERCA1a-expressing hearts ex vivo and in vivo. Am J Physiol Heart Circ Physiol 283: H958-H965, 2002; 10.1152/ ajpheart.00078.2002. -In this study we evaluated the contractile characteristics of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)1a-expressing hearts ex vivo and in vivo and in particular their response to ␤-adrenergic stimulation. Analysis of isolated, work-performing hearts revealed that transgenic (TG) hearts develop much higher maximal rates of contraction and relaxation than wild-type (WT) hearts. Addition of isoproterenol only moderately increased the maximal rate of relaxation (ϩ20%) but did not increase contractility or decrease relaxation time in TG hearts. Perfusion with varied buffer Ca 2ϩ concentrations indicated an altered dose response to Ca 2ϩ . In vivo TG hearts displayed fairly higher maximal rates of contraction (ϩ 25%) but unchanged relaxation parameters and a blunted but significant response to dobutamine. Our study also shows that the phospholamban (PLB) level was decreased (Ϫ40%) and its phosphorylation status modified in TG hearts. This study clearly demonstrates that increases in SERCA protein level alter the ␤-adrenergic response and affect the phosphorylation of PLB. Interestingly, the overall cardiac function in the live animal is only slightly enhanced, suggesting that (neuro)hormonal regulations may play an important role in controlling in vivo heart function. transgenic mice; contractility; sarco(endo)plasmic reticulum calcium adenosinetriphosphatase; phospholamban SEVERAL STUDIES HAVE SHOWN that sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA) activity is decreased in animal models of cardiac hypertrophy and failure as well as in human heart failure (11). This decrease in sarcoplasmic reticulum (SR) Ca 2ϩ transport function was thought to contribute to abnormalities in Ca 2ϩ handling and contractile dysfunction in failing hearts (14). Adenoviral gene transfer of SERCA is currently being explored as a new therapeutic approach for the treatment of heart failure (7,(26)(27)(28)(29).Recent studies have shown that the fast-twitch skeletal muscle isoform SERCA1 has a higher Ca 2ϩ uptake activity than the cardiac isoform SERCA2a because of a higher Ca 2ϩ turnover rate when expressed in cardiac myocytes (34). To test whether SERCA1a can functionally substitute for SERCA2a and increase cardiac contractility, we have developed a transgenic (TG) mouse model expressing SERCA1a in the heart (16,19,23). In this model, SERCA1a expression resulted in a 2.5-fold increase in total SERCA pump protein level, but the expression of the endogenous SERCA2a isoform was reduced to ϳ50% in TG hearts. As a consequence 20% of the total number of SERCA pumps in TG hearts were type 2a whereas the majority of 80% were type 1a pumps. The contractility of isolated TG hearts was clearly increased despite the reduced expression of SERCA2a (23). SERCA1a pump expression was well tolerated without any signs of hypertrophy or other pathophysiological changes in the...

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Section: Discussionmentioning

confidence: 54%

Altered dose response to β-agonists in SERCA1a-expressing hearts ex vivo and in vivo

Huke

Prasad

Nieman

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…In particular, PLB phosphorylation was decreased, which has been linked to dilated cardiomyopathy in humans (38) and associated with heart failure. However, the Pkd2 +/− mouse did not recapitulate phenotypes observed in mice with mutated PLB or troponin (39,40). Thus, the findings in the Pkd2 +/− mouse may reflect a compensatory pathway that has enabled an adaptation to altered calcium homeostasis without altering contractility through TnI phosphorylation.…”

Section: Discussionmentioning

confidence: 73%

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

Kuo¹,

Kwaczala

Nguyen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac disorders are the main cause of mortality in autosomaldominant polycystic kidney disease (ADPKD). However, how mutated polycystins predispose patients with ADPKD to cardiac pathologies before development of renal dysfunction is unknown. We investigate the effect of decreased levels of polycystin 2 (PC2), a calcium channel that interacts with the ryanodine receptor, on myocardial function. We hypothesize that heterozygous PC2 mice (Pkd2 +/− ) undergo cardiac remodeling as a result of changes in calcium handling, separate from renal complications. We found that Pkd2 +/− cardiomyocytes have altered calcium handling, independent of desensitized calcium-contraction coupling. Paradoxically, in Pkd2 +/− mice, protein kinase A (PKA) phosphorylation of phospholamban (PLB) was decreased, whereas PKA phosphorylation of troponin I was increased, explaining the decoupling between calcium signaling and contractility. In silico modeling supported this relationship. Echocardiography measurements showed that Pkd2 +/− mice have increased left ventricular ejection fraction after stimulation with isoproterenol (ISO), a β-adrenergic receptor (βAR) agonist. Blockers of βAR-1 and βAR-2 inhibited the ISO response in Pkd2 +/− mice, suggesting that the dephosphorylated state of PLB is primarily by βAR-2 signaling. Importantly, the Pkd2 +/− mice were normotensive and had no evidence of renal cysts. Our results showed that decreased PC2 levels shifted the βAR pathway balance and changed expression of calcium handling proteins, which resulted in altered cardiac contractility. We propose that PC2 levels in the heart may directly contribute to cardiac remodeling in patients with ADPKD in the absence of renal dysfunction.calcium signaling | β-adrenergic receptor blocker | excitation contraction coupling

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“…However, we found that, in the absence of ␤AR activation, AC VI gene transfer alone increased PLB phosphorylation on serine 16 ( Fig. 1, top 16) phosphorylation has been shown to be sufficient in mediating its maximal cardiac responses to ␤-agonists (13). The following studies were focused on determining the mechanisms for AC VI -associated Ser-16 phosphorylation of phospholamban.…”

Section: Resultsmentioning

confidence: 99%

Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes

Gao

Tang

Guo

et al. 2008

Journal of Biological Chemistry

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Increased expression of adenylyl cyclase VI has beneficial effects on the heart, but strategies that increase cAMP production in cardiac myocytes usually are harmful. Might adenylyl cyclase VI have beneficial effects unrelated to increased ␤-adrenergic receptor-mediated signaling? We previously reported that adenylyl cyclase VI reduces cardiac phospholamban expression. Our focus in the current studies is how adenylyl cyclase VI influences phospholamban phosphorylation. In cultured cardiac myocytes, increased expression of adenylyl cyclase VI activates Akt by phosphorylation at serine 473 and threonine 308 and is associated with increased nuclear phospho-Akt. Activated Akt phosphorylates phospholamban, a process that does not require ␤-adrenergic receptor stimulation or protein kinase A activation. These previously unrecognized signaling events would be predicted to promote calcium handling and increase contractile function of the intact heart independently of ␤-adrenergic receptor activation. We speculate that phospholamban phosphorylation, through activation of Akt, may be an important mechanism by which adenylyl cyclase VI increases the function of the failing heart. Adenylyl cyclase (AC) 4 catalyzes ATP to generate cAMP, a second messenger that is required for many intracellular events. AC is the effector molecule in the ␤-adrenergic receptor (␤AR)-Gs-AC signaling pathway and for many other G-protein-coupled receptors in cardiac myocytes and other cells (1-2). Cardiac myocytes express predominantly AC type V and AC type VI (AC VI ) (3). Cardiac-directed expression of AC VI in murine cardiomyopathy increases cardiac function, attenuates myocardial hypertrophy, and increases survival (4, 5). However, when cardiac-directed ␤AR expression is used in this same model, life is shortened (6, 7). Clearly there are marked differences in effects that are evoked by these two elements in the ␤AR-Gs-AC signaling pathway, even though both strategies increase cAMP.The objective of the current study was to determine whether increased AC VI expression has effects not directly linked with ␤AR stimulation and protein kinase A (PKA) activation, thereby providing a mechanistic explanation for the unanticipated favorable effects of increased cardiac AC VI expression in heart failure. We previously reported that AC VI reduces cardiac phospholamban (PLB) expression through increased expression of activating transcription factor-3, which suppresses PLB promoter activity (8). We now focus on how AC VI influences PLB phosphorylation. We test the hypothesis that AC VI increases PLB phosphorylation independently of ␤AR stimulation and PKA activation. This would result in increased cardiac function but would circumvent deleterious effects of sustained PKA activation (9).

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

Cited by 144 publications

References 41 publications

Altered dose response to β-agonists in SERCA1a-expressing hearts ex vivo and in vivo

Altered dose response to β-agonists in SERCA1a-expressing hearts ex vivo and in vivo

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes

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