In the early 1970s, a discovery was reported by Arnold Katz (Tada et al'), who demonstrated that phosphorylation of isolated cardiac sarcoplasmic reticulum membranes occurred mainly on a low molecular weight protein. This phosphoprotein was named phospholamban, from the Greek root words meaning" to receive phosphate."'Phospholamban is a small protein, comprising 52 amino acid residues, and it is present in cardiac, smooth, and slowtwitch skeletal muscles. However, its regulatory effects have been mainly studied in cardiac muscle. In vitro studies indicated that phospholamban can be phosphorylated at three distinct sites by various protein kinases: serine 10, by protein kinase C; serine 16, by cAMP-or cGMP-dependent protein kinase; and threonine 17, by Ca2+-calmodulin-dependent protein kinase. 2-3 Each phosphorylation is associated with stimulation of the initial rates of cardiac sarcoplasmic reticulum Ca2+ uptake, which is mainly pronounced at low [Ca2+], resulting in an overall increase in the affinity of the Ca2+ pump for Ca2+. 4-5 On the basis of these observations, it was initially hypothesized that phosphorylated phospholamban functions as a stimulator of the cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2) enzyme. However, in the late 1980s, a significant breakthrough occurred demonstrating that dephosphorylated phospholamban is actually an inhibitor of cardiac sarcoplasmic reticulum Ca2+ transport for Ca2+ and that phosphorylation relieves this inhibitory effect, giving the appearance of phosphorylation-induced stimulation. 6 This finding, together with the identification of a cardiac sarcoplasmic reticulum-associated protein phosphatase that can dephosphorylate phospholamban, 7 has led to our current understanding of phospholamban as a reversible inhibitor of the cardiac sarcoplasmic reticulum Ca2+ ATPase activity.