Disease relevance of Pln

• The results demonstrated a dissociation between the phosphorylation of PLB sites, being phosphorylation of Ser(16)dependent on the beta-adrenergic cascade during ischemia and phosphorylation of Thr(17)on Ca(2+)influx both, at the beginning of ischemia and reperfusion [1].
• Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury [2].
• Paraplegia significantly increased the relative protein abundances of SERCA (45%) and the Na/Ca exchanger (40%) and decreased phospholamban levels (-28%) [3].
• These findings indicate that IHA hypoxia mitigates I/R-induced depression in SR Ca(2+)-pump ATPase activity by upregulating dual-site PLB phosphorylation, which may consequently contribute to IHA hypoxia-induced cardioprotection against I/R injury [2].
• The decrease in phospholamban phosphorylation during late sepsis was accompanied by decreases in Ca2+ transport, LVDP, +/-dP/dt(max), and tissue cAMP content [4].

Psychiatry related information on Pln

• The high variability of responses of slow-twitch muscles to beta2-agonists probably reflects individual differences in basal phosphorylation levels of PLB relative to that of RR [5].

High impact information on Pln

• Ablation or inhibition of phospholamban (PLN) has favorable effects in several genetic murine dilated cardiomyopathies, and we showed previously that a pseudophosphorylated form of PLN mutant (S16EPLN) successfully prevented progressive heart failure in cardiomyopathic hamsters [6].
• Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats [6].
• The receptor is confined to the sarcoplasmic reticulum (SR) where it is localized to interior and peripheral junctional SR and the corbular SR, but it is absent from the network SR where the SR-Ca(2+)-ATPase and phospholamban are densely distributed [7].
• We used a catheter-based technique to achieve generalized cardiac gene transfer in vivo and to alter cardiac function by overexpressing phospholamban (PL) which regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) [8].
• Depletion of Ca2+ from the sarcoplasmic reticulum of cardiac muscle prompts phosphorylation of phospholamban to stimulate store refilling [9].

Chemical compound and disease context of Pln

• Measurement of cardiac hypertrophy, diastolic function, and sarcoendoplasmic reticulum adenosine triphosphatase (ATPase; SERCA) and phospholamban (PLB) gene expression was assessed at 6 weeks after MI [10].
• Mechanisms involved in the acidosis enhancement of the isoproterenol-induced phosphorylation of phospholamban in the intact heart [11].
• Here we show that inhibition of G(i) proteins with pertussis toxin (PTX) permits a full phospholamban phosphorylation and a de novo relaxant effect following beta(2)-AR stimulation, converting the localized beta(2)-AR signaling to a global signaling mode similar to that of beta(1)-AR [12].
• In this study, we examined the effects of long-term treatment of imidapril on mortality, cardiac function, and gene expression for SL Na+/K+ ATPase and Na+ -Ca2+ exchanger as well as SR Ca2+ pump ATPase, Ca2+ release channel (ryanodine receptor), phospholamban, and calsequestrin in CHF due to myocardial infarction [13].
• This study examined the effects of long-term treatments with the angiotensin-converting enzyme inhibitor, enalapril, and the calcium antagonist, amlodipine, on the morphologic changes, progressive left ventricular dysfunction, and gene expression of the ryanodine receptor (RyR) and phospholamban (PLN) in dilated cardiomyopathy [14].

Biological context of Pln

• We determined that the cAMP-responsive-like element in the phospholamban (PLB) promoter was critical for down-regulation by AC(VI) [15].
• The goal of the current study was to investigate the efficacy of the RNAi method for ablation of PLB gene expression and restoration of Ca(2+) uptake function in cultured neonatal rat cardiac myocytes in which SERCA2 protein levels were decreased [16].
• Administration of PLB siRNA resulted in the reduction of PLB mRNA level to approximately 6% of that observed after administration of scramble siRNA group at 12 h after transfection [16].
• Phospholamban ablation by RNA interference increases Ca2+ uptake into rat cardiac myocyte sarcoplasmic reticulum [16].
• No SLN was found in the ventricles of the different species studied, and there was no compensatory SLN up-regulation for the loss of PLB in PLB(-/-) mouse [17].

Anatomical context of Pln

• We found that overexpression of AC(VI) down-regulated mRNA and protein expression of phospholamban, an inhibitor of the sarcoplasmic reticulum Ca(2+)-ATPase [15].
• Following AC(VI) gene transfer, when cardiac myocytes were stimulated with isoproterenol or NKH477, a water-soluble forskolin analog that directly stimulates AC, expression of ATF3 protein was increased even more, which correlated with reduced expression of PLB [15].
• Myocytes were transfected with 21-nucleotide duplexes of small interfering RNA (siRNA) targeting PLB (30 nmol/l) or with scramble sequence using a haemagglutinating virus of Japan (HVJ) envelope vector [16].
• Thyroid hormone exerts positive inotropic effects on the heart mediated in part by its regulation of calcium transporter proteins, including sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2), phospholamban (PLB), and Na(+)/Ca(2+) exchanger (NCX) [18].
• Our data confirm the co-expression of PLB and SERCA2a in cardiac muscle and the very low levels (in pig and rabbit) or the absence (in rat and mouse) of PLB protein in the slow skeletal muscle [17].

Associations of Pln with chemical compounds

• We further demonstrate that SLN is localized within the SR membrane similar to PLB and SR Ca(2+) ATPase [19].
• Furthermore, triamcinolone treatment resulted in reduced levels of SERCA2a (-40 %, P < 0.05) and increased levels of SLN mRNA (+100 %, P < 0.05), while the decrease in PLB mRNA (-31 %, P = 0.277) did not reach statistical significance [20].
• Thyroid hormone control of contraction and the Ca(2+)-ATPase/phospholamban complex in adult rat ventricular myocytes [21].
• Also, insulin treatment almost completely normalized phosphorylation of PLB at threonine 17 in female diabetic rats; however, the increase was significantly greater than that identified for insulin-treated male diabetic rats [22].
• Insulin treatment completely normalized blood glucose level, cardiac SERCA2a and PLB protein levels, and the decrease in MHC-beta levels in both male and female diabetic rats [22].

Enzymatic interactions of Pln

• In hypertrophic hearts, quantitative immunoblotting analyses showed increased levels both of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and phosphorylated phospholamban, along with decreased levels of total phospholamban, which is in line with strengthened right ventricular systolic function [23].

Regulatory relationships of Pln

• Finally, PLB siRNA restored Ca(2+) uptake affinity following hydrogen peroxide-induced decreases in SERCA2 and PLB mRNA expression [16].
• Phospholamban forms an integral part of the cardiac sarcoplasmic reticulum (SR) and regulates the activity of SR Ca(2+)-ATPase (SERCA2a) [24].
• Finally, CPA-induced dephosphorylations of troponin I and phospholamban were blocked by pertussis toxin and attenuated by p38 MAPK inhibition [25].
• The calmodulin antagonist W-7 significantly decreased the isoproterenol-induced phosphorylation of phospholamban at [Ca]o 1.35 mM [26].

Other interactions of Pln

• Adenylyl cyclase type VI gene transfer reduces phospholamban expression in cardiac myocytes via activating transcription factor 3 [15].
• Phospholamban protein content was significantly reduced by 33% but SR-Ca(2+)-ATPase protein content was not significantly altered in T3-cells [21].
• Cell phenotype was determined by immunoblot and immunocytofluorescence using antisera specific for the differentiation markers alpha-actin, myosin, calponin, osteopontin, and phospholamban [27].
• Thus, the levels of expression of beta-myosin heavy chain and atrial natriuretic factor mRNA increased, of sarcoplasmic/endoplasmic reticulum ATPase (SERCA2) mRNA decreased, and of alpha-myosin heavy chain, phospholamban, and calsequestrin mRNA did not change [28].
• METHODS AND RESULTS: Part of the PL cDNA was cloned in antisense and sense directions into adenovectors under the control of either a CMV (Ad5CMVPLas and Ad5CMVPLs, respectively) or ANF (Ad5ANFPLas and Ad5ANFPLs, respectively) promoter [29].

Analytical, diagnostic and therapeutic context of Pln

• Co-immunoprecipitation studies indicate that SLN can physically interact with phospholamban [19].
• Atrial and left ventricular (LV) tissue homogenates were analyzed for expression of SERCA2, PLB, and NCX proteins by Western blot analysis [18].
• Northern blot analysis revealed reciprocal alterations in the expression of SERCA2 and phospholamban [21].
• Quantitative immunoblotting in combination with affinity-purified protein standards was used to measure protein concentrations of PLB and of the Ca-ATPase [30].
• Although the PLB protein levels remained constant during I/R in both groups, Ser(16) phosphorylation increased at I30 and 1 min of reperfusion (R1) but decreased at R30 in normoxic hearts [2].

References