Disease relevance of PLN

• Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca(2+)-ATPase protein levels. Effects on Ca2+ transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure [1].
• OBJECTIVE: The aim was to determine whether changes in sarcoplasmic reticular Ca2+ transport activity and the degree of phosphorylation of phospholamban of "stunned" myocardium are involved in the reversible depression of contractile function [2].
• It is postulated that the ischemia induced inactivation of the Ca2+ pump is not only a consequence of specific loss of enzyme activity, but it is also caused by altered characteristics of phospholamban [3].
• It is concluded that the reductions by carbachol and (-)-N6-phenylisopropyladenosine of isoproterenol-stimulated PLB phosphorylation and Tnl phosphorylation are pertussis toxin-sensitive [4].
• Purification of porcine phospholamban expressed in Escherichia coli [5].

High impact information on PLN

• Administration of 0.1 or 0.3 mumol/L Levosimendan significantly increased myocardial cAMP levels as well as the phosphorylation of phospholamban, troponin I, and C protein [6].
• The EC50 value for isoproterenol to phosphorylate phospholamban was 8 +/- 1 nM (n = 3), which increased to 31 +/- 4 nM (n = 3) in the presence of PIA or NECA [7].
• Isoproterenol (10 nM, 37 degrees C, 10 seconds) increased cAMP content (236%) and phospholamban (265%) and troponin I (135%) phosphorylation in ventricular myocytes [7].
• We conclude that phospholamban phosphorylation was inhibited by A1-adenosine receptor activation and that these effects on phospholamban phosphorylation cannot be explained by a reduction in cAMP levels [7].
• IC50 values for PIA or NECA to decrease the phosphorylation of phospholamban were 30 or 32 nM in 10 nM isoproterenol-stimulated cells and 80 or 85 nM in 30 nM isoproterenol-stimulated cells [7].

Chemical compound and disease context of PLN

• Elevated levels of endogenous adenosine alter metabolism and enhance reduction in contractile function during low-flow ischemia: associated changes in expression of Ca(2+)-ATPase and phospholamban [8].
• The in vitro 32P incorporation into phospholamban in the presence of cAMP plus the catalytic subunit of cyclic AMP dependent protein kinase became markedly reduced depending on the duration of ischemia [3].

Biological context of PLN

• The amino acid sequences of these two tryptic peptides corresponded exactly to residues 14-25 and 15-25 of canine cardiac phospholamban, thus localizing the sites of in situ phosphorylation to serine 16 and threonine 17 [9].
• Thus, it appears that Ca2+-binding site I of calmodulin is at or near binding sites of calmodulin for TnI, TnT, and phospholamban [10].
• On the other hand, the fluorescence intensity decay of bound dansyl is sensitive to the phosphorylation state of PLB, indicating that there are changes in the tertiary structure of PLB coincident with enzyme activation [11].
• In vitro cyclic AMP induced phosphorylation of phospholamban: an early marker of long-term recovery of function following reperfusion of ischaemic myocardium [12]?
• There was insignificant downregulation of sarcoplasmic reticulum adenosine triphosphatase and phospholamban after 1, 3, and 7 days [13].

Anatomical context of PLN

• We have performed molecular dynamics simulations of phospholamban (PLB), a 52-residue integral membrane protein that inhibits calcium ATPase in the cardiac sarcoplasmic reticulum [14].
• This peptide shares 100% sequence identity with dog cardiac-muscle phospholamban [15].
• cDNA cloning and sequencing of phospholamban from pig stomach smooth muscle [15].
• It differs from rabbit cardiac-muscle and slow-twitch skeletal-muscle phospholamban only at position 2, which is a glutamic acid residue in rabbit phospholamban, but an aspartic acid residue in the pig smooth-muscle protein [15].
• Examination of the 32P incorporation into various fractions revealed that there were no increases in the degree of phosphorylation of phospholamban in sarcoplasmic reticulum, and troponin I and C protein in the myofibrils, although these proteins were found to be substrates for protein kinase C in vitro [16].

Associations of PLN with chemical compounds

• In the simulations of PLB in methanol and water, the helices were almost perpendicular, with average interhelix angles of 54 +/- 13 degrees and 63 +/-15 degrees , respectively [14].
• Both adenosine receptor agonists failed to inhibit the phosphorylation of troponin I. However, acetylcholine (2 microM) in the presence of 10 nM isoproterenol inhibited phosphorylation of phospholamban as well as troponin I in ventricular cells [7].
• Milrinone (50 microM) produced a 2.5-fold increase in cAMP levels but failed to change phospholamban phosphorylation [17].
• The incorporation of 32Pi into phospholamban, troponin I, phosphatidylinositols, and inositol trisphosphates was studied in Langendorff-perfused guinea pig hearts stimulated with isoproterenol [18].
• The influence of selective (milrinone: 10, 50, 100 microM) and nonselective phosphodiesterase (isobutylmethylxanthine: 0.1, 10, 100 microM) inhibitors and beta-adrenergic stimulation (isoproterenol: 0.01, 0.1 microM) on phospholamban and myofibrillar protein phosphorylation was studied in guinea pig hearts perfused with [32P]orthophosphate [17].

Other interactions of PLN

• Phospholamban, a regulator of the SERCA2 Ca2(+)-transport ATPase in cardiac/slow-twitch skeletal/smooth muscle, could not be detected in Purkinje neurons [19].
• We tested the hypothesis that activation of protein kinase C (PKC) isoforms in pressure-overload heart failure was prevented by angiotensin-converting enzyme (ACE) inhibition, resulting in normalization of cardiac sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) 2a and phospholamban protein levels and improvement in intracellular Ca2+ handling [20].
• Regional alterations in SR Ca(2+)-ATPase, phospholamban, and HSP-70 expression in chronic hibernating myocardium [21].

Analytical, diagnostic and therapeutic context of PLN

• Northern-blot analysis reveals the presence of several phospholamban mRNAs in smooth muscle, but a 900-nucleotide-residue and a 2800-nucleotide-residue transcript predominate [15].
• The cardiac mechanical and morphometric changes were associated with depressed protein levels of the SR Ca(2+)-ATPase (85% of the control) and phospholamban (65% of the control) assessed by quantitative immunoblotting [1].
• In these same hearts, perfusion with 0.03 mumol/L Levosimendan did not alter the 32P incorporation into troponin I or C protein, whereas a slight but significant increase was noted for phospholamban, with no detectable change in tissue cAMP levels [6].
• The differential expression of phospholamban was also confirmed on Western blots [22].
• The steady state level of phospholamban mRNA rose 2.5-fold at 180 min of reperfusion [23].

References