Role of regucalcin in brain calcium signaling: involvement in aging

Abstract

Regucalcin was discovered in 1978 to be a calcium-binding protein that does not contain the EF-hand motif of the calcium-binding domain [M. Yamaguchi and T. Yamamoto, Chem. Pharm. Bull., 26, 1915–1918, 1978]. The regucalcin gene is localized on the X chromosome and its expression is enhanced through various transcription factors. Regucalcin is known to play a multifunctional role as a suppressor protein of cell signaling in many cell types. Regucalcin is expressed in rat brain neurons and it is decreased in the cerebral cortex and hippocampus of the brain with aging. Neuronal Ca²⁺ signaling has been implicated in mechanisms of neuronal plasticity like long-term potentiation, which is likely to play an important role in learning and memory. The disturbance of brain Ca²⁺ homeostasis may play a pivotal role in the revelation of brain disease. The intracellular Ca²⁺ in brain tissues is increased with aging. Aging enhances the entry of Ca²⁺ into brain neuronal cells across the plasma membranes. An increase in the brain microsomal Ca²⁺-ATPase activity of rats with aging resulted in calcium accumulation in the microsomes of the Ca²⁺-sequestrating system that is partly related to the brain toxicity by calcium. Regucalcin had an inhibitory effect on rat brain microsomal Ca²⁺-ATPase activity. The suppressive effect of regucalcin on brain microsomal Ca²⁺-ATPase activity was weakened in aged rats. Regucalcin was found to inhibit brain cytosolic protein kinase C. Brain microsomal Ca²⁺-ATPase activity was enhanced by protein kinase C in aged rats. Regucalcin could also inhibit activity of Ca²⁺/calmodulin-dependent protein kinase, protein phosphatase, and Ca²⁺/calmodulin-dependent nitric oxide synthase, which is linked to Ca²⁺ signaling, in the cytosol of rat brain neurons. These inhibitory effects of regucalcin were weakened with aging. Regucalcin may play a pivotal role in the regulation of Ca²⁺ signaling which is stimulated through a neurotransmitter in the brain neurons with aging.