Phospholamban Gene Dosage Effects in the Mammalian Heart

Abstract

Phospholamban ablation has been shown to result in significant increases in cardiac contractile parameters and loss of beta-adrenergic stimulation. To determine whether partial reduction in phospholamban levels is also associated with enhancement of cardiac performance and to further examine the sensitivity of the contractile system to alterations in phospholamban levels, hearts from wild-type, phospholamban-heterozygous, and phospholamban-deficient mice were studied in parallel at the subcellular, cellular, and organ levels. The phospholamban-heterozygous mice expressed reduced cardiac phospholamban mRNA and protein levels (40 +/- 5%) compared with wild type mice. The reduced phospholamban levels were associated with significant decreases in the EC50 of the sarcoplasmic reticulum Ca2+ pump for CA2+ and increases in the contractile parameters of isolated myocytes and beating hearts. The relative phospholamban levels among wild-type, phospholamban-heterozygous, and phospholamban-deficient mouse hearts correlated well with the (1) EC50 of the Ca(2+)-ATPase for Ca2+ in sarcoplasmic reticulum, (2) rates of relaxation and contraction in isolated cardiac myocytes, and (3) rates of relaxation and intact beating hearts. These findings suggest that physiological and pathological changes in the levels of phospholamban will result in parallel changes in sarcoplasmic reticulum function and cardiac contraction.

Tropomyosin Dephosphorylation Results in Compensated Cardiac Hypertrophy

“…4, A and B). Additionally, there are no significant differences in pCa 50 or the Hill coefficient (n H ), a measure of the cooperative activation of the thin filament of the sarcomere.…”

Atrial Chamber-specific Expression of Sarcolipin Is Regulated during Development and Hypertrophic Remodeling

“…The expression level of PLN directly affects cardiac contractility and relaxation in the heart (23,24). SLN also inhibits Ca 2ϩ uptake at low Ca 2ϩ concentrations like PLN but enhances Ca 2ϩ uptake at high Ca 2ϩ concentrations (3,25).…”

Lethal, Hereditary Mutants of Phospholamban Elude Phosphorylation by Protein Kinase A

“…For this, we returned to the disease-associated R9C mutant, which could not be phosphorylated by PKA in our assays and thus provided a rigorous test for our hypothesis. A full-length monomeric form of R9C (R9C-SSS) and an R9C cytoplasmic peptide (R9C [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] , amino acids 1-20 of PLN) were both tested for their ability to be phosphorylated by PKA. The monomeric form of PLN was generated by replacing the three transmembrane cysteine residues (Cys 36 , Cys 41 , and Cys 46 ) with serine.…”