Role of regucalcin in calcium signaling.

Regucalcin was discovered in 1978 as a calcium-binding protein that does not contain EF-hand motif of Ca(2+)-binding domain [M. Yamaguchi and T. Yamamoto, Chem. Pharm. Bull. 26 1915-1918 (1978)]. In recent years, regucalcin has been demonstrated to play an important role as a regulatory protein in Ca2+ signaling in rat liver and kidney cells. The organization of the rat regucalcin gene consists of seven exons and six introns. The mRNA is mainly present in liver and kidney with a size of 1.8 kb. Hepatic regucalcin mRNA expression has been shown to be stimulated by various factors including calcium, calcitonin, insulin, and estrogen in rats. The mRNA is also expressed in hepatoma cells (Morris hepatoma, HepG2, and rat hepatoma H4-II-E cells). Regucalcin plays a role in the maintenance of intracellular Ca2+ homeostasis due to activating Ca2+ pump enzymes in the plasma membrane (basolateral membrane) and microsomes of liver and renal cortex cells. Moreover, regucalcin has an inhibitory effect on the activation of Ca2+/calmodulin-dependent enzymes and protein kinase C. Also, regucalcin has been demonstrated to regulate nuclear function in liver cells; it can inhibit Ca(2+)-activated DNA fragmentation, DNA and RNA synthesis, protein kinase and protein phosphatase activities in the nuclei. Such an effect is also seen in the nuclei of regenerating rat liver. Regucalcin may play a physiological role in the control for overexpression of proliferative cells. Regucalcin has been proposed to be an important regulatory protein in Ca2+ signaling system, and it plays a multifunctional role in liver and kidney cells.