Sarcolipin (SLN), a key regulator of cardiac sarco(endo)plasmic reticulum (SR) Ca2+ ATPase, is predominantly expressed in atria and mediates beta-adrenergic responses. Studies have shown that SLN mRNA expression is decreased in human chronic atrial fibrillation (AF) and in aortic banded mouse atria; however, SLN protein expression in human atrial pathology and its role in atrial SR Ca2+ uptake are not yet elucidated. In the present study, we determined the expression of major SR Ca2+ handling proteins in atria of human AF patients and in human and in a mouse model of heart failure (HF). We found that the expression of SR Ca2+ uptake and Ca2+ release channel proteins are significantly decreased in atria but not in the ventricles of pressure-overload induced HF in mice. In human AF and HF, the expression of SLN protein was significantly decreased; whereas the expressions of other major SR Ca2+ handling proteins were not altered. Further, we found that the SR Ca2+ uptake was significantly increased in human AF. The selective downregulation of SLN and enhanced SR Ca2+ uptake in human AF suggest that SLN downregulation could play an important role in abnormal intracellular Ca2+ cycling in atrial pathology. (C) 2011 Elsevier Inc. All rights reserved.