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 Ca(2+) 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 Ca(2+) homeostasis may play a pivotal role in the revelation of brain disease. The intracellular Ca(2+) in brain tissues is increased with aging. Aging enhances the entry of Ca(2+) into brain neuronal cells across the plasma membranes. An increase in the brain microsomal Ca(2+)-ATPase activity of rats with aging resulted in calcium accumulation in the microsomes of the Ca(2+)-sequestrating system that is partly related to the brain toxicity by calcium. Regucalcin had an inhibitory effect on rat brain microsomal Ca(2+)-ATPase activity. The suppressive effect of regucalcin on brain microsomal Ca(2+)-ATPase activity was weakened in aged rats. Regucalcin was found to inhibit brain cytosolic protein kinase C. Brain microsomal Ca(2+)-ATPase activity was enhanced by protein kinase C in aged rats. Regucalcin could also inhibit activity of Ca(2+)/calmodulin-dependent protein kinase, protein phosphatase, and Ca(2+)/calmodulin-dependent nitric oxide synthase, which is linked to Ca(2+) 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 Ca(2+) signaling which is stimulated through a neurotransmitter in the brain neurons with aging.

Regucalcin Expression in Bovine Tissues and Its Regulation by Sex Steroid Hormones in Accessory Sex Glands

“…As the name suggests, RGN regulates intracellular Ca 2+ homeostasis through the modulation of the activity of Ca 2+ channels, Ca 2+ -ATPase in the membrane of mitochondria and endoplasmic reticulum [4], [5] and (Ca 2+ -Mg 2+ )-ATPase in the plasma membrane [6], [7]. Moreover, RGN plays an important role in the regulation of Ca 2+ -dependent enzymes, such as protein kinases, tyrosine kinases, phosphatases, phosphodiesterase, nitric oxide synthase and proteases [8]–[13].…”

“…RGN is widely expressed in a variety of tissues and cell lines [25]–[27] and was first identified in the liver, where this protein is highly expressed [1]. However, RGN mRNA and/or protein expression has also been detected in the male and female reproductive tract [23], [28]–[29], submandibular glands [30], several brain districts [13], [31]–[32], the heart [33]–[34], skeletal muscle [35], lung [36], kidney [35], [37], adrenal glands [19], bone [38]–[39]. RGN protein has been also shown to be secreted to biological fluids, namely plasma [31], [40]–[41] and seminiferous tubules fluid [29].…”

Effects of pterostilbene and resveratrol on brain and behavior

“…Oxidative damage, alteration in Ca 2þ homeostasis, and loss of autophagy function in the brain cause disruption in numerous signaling pathways and alterations in protein homeostasis, which contribute to the loss of cognitive function during aging (Poulose et al, 2014b;Thibault et al, 2007;Yamaguchi, 2012). Both RES and PTE have been shown to protect cells from oxidative stress, excitotoxicity, and dysregulation of autophagy (Jeong et al, 2012;Ko et al, 2015).…”

Calcium Regulatory Protein, Regucalcin, may be a Key Molecule in Brain Disease

“…Regucalcin has been shown to have an inhibitory effect on Ca Page 2 of 3 and phosphothreonine in rat brain cytoplasm and neurons [21,26]. Calbindin and S-100A proteins, which are Ca 2+ -binding protein in brain [11], have no effect on protein phosphatase activity in rat brain cytoplasm [26]. Regucalcin is localized in the microsomes of rat brain, and aging causes a decrease in the microsomal regucalcin levels [27].…”

“…Interestingly, the map location for a growing number of diseases with a genetic basis is encompassed in human X chromosome, and these are known to include syndromic and non-syndromic forms of X-linked mental retardation and X-linked neuromuscler diseases [9]. Regucalcin is expressed in rat brain neuron, and it is decreased in the cerebral cortex and hippocampus of brain with aging [10,11]. There is growing evidence that regucalcin plays a pivotal role in brain neuronal cell regulation.…”