Control of the calcium pump of cardiac sarcoplasmic reticulum. A specific role for the pentameric structure of phospholamban?

Intracellular sources of calcium provide most of that required for cardiac muscle contraction. Regulation of the filling of these calcium stores by control of the enzyme responsible for calcium uptake, the sarcoplasmic reticular calcium pump, provides a mechanism by which the contractile properties of the heart can be adapted. In fact, this single biochemical event accounts for most of the changes in calcium handling associated with beta adrenergic stimulation. The calcium pump of cardiac sarcoplasmic reticulum is regulated by the phosphorylation status of a second sarcoplasmic reticular component, phospholamban. This is a low molecular weight membrane protein which assembles as an oligomer (homopentamer) and inhibits pump function by physical interaction with a "regulatory" motif on the pump. This interaction (and the state of inhibition) is broken following phosphorylation of phospholamban by cAMP-, cGMP, or Ca2+/calmodulin dependent protein kinases. This model of pump control shares a number of features associated with control of the plasma membrane calcium pump; however, the oligomeric arrangement of the regulator is specific for the sarcoplasmic reticular ATPase. The functional significance of the oligomer is currently unknown, but this format may provide functional advantages such as (1) offering an effective substrate structure for kinase/phosphatase, promoting rapid changes in phosphate status; (2) facilitating intrapentamer cooperation, translating low stoichiometric phosphorylation into large changes in pump function; or (3) coordinating multiple pump units around a single pentamer thus restricting conformational freedom and suppressing enzyme activity.