Calreticulin, a Multifunctional Ca²⁺ Binding Protein of Smooth Muscle Sarcoplasmic Reticulum Membranes

Abstract

Ca²⁺ is a second messenger that controls a wide variety of cellular functions, including the regulation of metabolic pathways; the synthesis and release of hormones and neurotransmitters; muscle and nonmuscle motility; lipid and carbohydrate metabolism; apoptosis; and mitosis [1]. Because of its multiple action, there is a stringent requirement for the maintenance of cytosolic Ca²⁺ at submicromolar concentrations. This is achieved by a system of Ca²⁺-transport and storage pathways that includes Ca²⁺-buffering proteins in the cytosol and in the lumen of intracellular storage compartments such as endoplasmic reticulum (ER) in nonmuscle cells and sarcoplasmic reticulum (SR) in muscle cells. In nonmuscle ER, there are several Ca²⁺ binding proteins, of which a major Ca²⁺ binding protein is calreticulin [2–5]. Calreticulin binds Ca²⁺ with both high affinity/low capacity (K _d = ~1 µM, B _max = 1 mole of Ca²⁺/mole of protein) and low affinity/high capacity (K _d = ~250 µM, B _max = 25 moles of Ca²⁺/mole of protein) [6,7]. Given this high binding capacity, it is likely that calreticulin functions as a Ca²⁺ storage protein in the lumen of the SR/ER [4], and therefore likely that calreticulin plays an important role in the control of cytoplasmic Ca²⁺ concentrations. In cardiac and skeletal muscle SR membranes, the major Ca²⁺-binding storage/ protein is calsequestrin [3,8].