A comprehensive discussion is presented of advances in understanding the structure and function of phospholamban (PLB), the principal regulator of the Ca2+-ATPase of cardiac sarcoplasmic reticulum. Extensive historical studies are reviewed to provide perspective on recent developments. Phospholamban gene structure, expression, and regulation are presented in addition to in vitro and in vivo studies of PLB protein structure and activity. Applications of breakthrough experimental technologies in identifying PLB structure-function relationships and in defining its interaction with the Ca2+-ATPase are also highlighted. The current leading viewpoint of PLB's mechanism of action emerges from a critical examination of alternative hypotheses and the most recent experimental evidence. The potential physiological relevance of PLB function in human heart failure is also covered. The interest in PLB across diverse biochemical disciplines portends its continued intense scrutiny and its potential exploitation as a therapeutic target.

Phospholamban is a phosphoprotein regulator of cardiac sarcoplasmic reticulum which is phosphorylated in response to ␤-adrenergic stimulation. Previous results have shown that phospholamban forms Ca 2؉ -selective channels in lipid bilayers. The channel-forming domain has been localized to amino acid residues 26 -52, which form a stable pentameric, helical structure. The specific residues responsible for stabilizing the pentameric membrane domain of phospholamban have been identified by mutational analysis.

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