Introduction phorylation of its inhibitor protein. 11, 12 In SDS polyacrylamide gels, PLB migrates pre-The sarcoplasmic reticulum (SR) is an intracellular membranous network, which plays an essential dominately as a pentamer (> 25–28kDa), but it dissociates into monomers (> 6 kDa) upon boiling. 13 role in mediating contraction and relaxation in the adult cardiomyocyte. During contraction, the SR The PLB monomer consists of 52 amino acids and is proposed to contain three domains:(a) cytosolic serves as a reservoir for Ca2+ while, during relaxation, it functions as a Ca2+ sink. Sequestration domain IA (amino acid residues 1–20);(b) cytosolic domain IB (amino acid residues 21–30); and (c) of Ca2+ from the cytosol into the SR lumen is mediated by the SR Ca2+-ATPase (SERCA2). This transmembrane domain II (amino acid residues 31–52). 7 Structure/function investigations on PLB enzyme is under the regulatory control of the phosphoprotein phospholamban (PLB), which has been suggested that there are two and possibly three sites through which PLB interacts with SERCA2. 14–16 shown to inhibit the apparent Ca2+-affinity of SERCA2 in its dephosphorylated form. 1, 2 The mech- Electrostatic and hydrophobic interactions between domain IA of PLB and SERCA2 have been proposed anism of action and functional significance of PLB have been well-characterized in cardiac muscle to play an important role in the functional association between these two proteins, and may because of its abundant expression in cardiac SR. However, low expression of PLB has also been modulate the transmembrane inhibitory actions. 14 PLB domain II functions as an inhibitory domain detected in slow-twitch skeletal muscle, 3, 4 smooth muscl e 5 and a non-muscle tissue, the vascular endo- that regulates the apparent affinity of SERCA2 for Ca2+. 15 Domain IB has been suggested to regulate thelium. 6 In vitro studies, using purified cardiac SR membranes, have shown that PLB can be phos- the long-range coupling between domains IA and II of PLB, 15 but recent studies have shown that phorylated at three distinct sites by various protein kinases: Ser16, by cAMP-dependent protein kinase; this domain may also be involved in regulatory interactions between PLB and SERCA2. 16 Based on Thr17, by Ca2+/calmodulin-dependent protein kinase; and Ser10, by protein kinase C. 7 Phos- these findings, PLB and SERCA2 interactions have been proposed to occur via a four (or possibly six) phorylation at each of these sites is associated with stimulation of the initial rates of SR Ca2+-transport, base circuit, through which long-range inhibitory interactions are propagated among a series of cytoespecially at low or diastolic Ca2+ concentrations. 8–10 The stimulatory effects of PLB phos- plasmic and transmembrane interaction sites. 17 This review summarizes the recent advances on phorylation at these sites can be reversed by a cardiac SR-associated type 1 protein phosphatase, the physiological role of PLB in SR function and