Abstract 1233: Sarcolipin Regulates Atrial Calcium Transport and Contractility
arcolipin (SLN) is a small molecular weight protein, co-localized with SERCA pump in the sarcoplasmic reticulum (SR) membrane. In the heart, SLN expression is abundant in the atria but very low in the ventricle, opposite of PLB which is low in the atria and high in the ventricle. To determine the role of sarcolipin in SR calcium handling and cardiac contractility, we have generated two mouse models:
cardiac specific overexpression of SLN and
SLN knockout. Overexpression or complete loss of SLN did not affect the cardiac muscle development or induce any cardiac pathology.
Overexpression of sarcolipin decreases calcium-dependent calcium uptake, whereas ablation of SLN increases the calcium uptake in both atria and ventricle. An increase in the Vmax of calcium uptake in SLN null atria indicates that the SLN may affect SERCA pump kinetics. Work-performing heart preparations showed that loss of SLN significantly increases the rates of contraction and relaxation, whereas an increase in SLN level decreases the contractility. SLN null hearts showed blunted response to isoproterenol treatment. On the other hand, the inhibitory effect of SLN was relieved upon high dose of isoproterenol in SLN overexpressing hearts, which may suggest that SLN also mediates beta-adrenergic response. Biochemical characterization of these mouse models suggest that increased or absence of SLN does not affect the expression of other major calcium handling proteins, including SERCA, phospholamban, calsequestrin, ryanodine receptor, sodium calcium exchanger and L-type calcium channel. Further, SLN levels did not affect the monomer to pentamer ratio and basal phosphorylation of PLB indicating that SLN action on SERCA pump is independent of PLB. Taken together, our results suggest that SLN is an important regulator of SR calcium ATPase in the atria and can act as a mediator of beta-adrenergic response. We also found that SLN expression levels are increased 3 fold in the atria of heart failure dogs. Studies are underway to determine the role of SLN in atrial physiology and its potential role in pressure overload induced heart failure using the genetically altered mouse models.