a ular nd G ec en l e o t i M c f M o l e Journal of Molecular and Genetic d a i Yamaguchi, J Mol Genet Med 2013, 7:4 n c r i n u e o DOI: 10.4172/1747-0862.1000087 J Medicine ISSN: 1747-0862 EditorialResearch Article OpenOpen Access Access Calcium Regulatory Protein, Regucalcin, may be a Key Molecule in Brain Disease Masayoshi Yamaguchi* Department of Hematology and Medical Oncology, Emory University School of Medicine,, Atlanta, USA Regucalcin was discovered in 1978 as a novel calcium-binding microsomal Ca2+ATPase activity [18]. Regucalcin has been found to protein [1-4]. Regucalcin (RGN) and its gene (rgn) are identified in have an inhibitory effect on brain microsomal Ca2+-ATPase activity over 15 species of vertebrate and invertebrates consisting of regucalcin [10]. Brain microsomal Ca2+-ATPase activity is not significantly altered family [5]. Regucalcin plays a multifunctional role in cell regulation; by calmodulin, calbindin or S-100A protein, which are Ca2+-binding maintaining of intracellular calcium (Ca2+) homeostasis, suppressions proteins in brain [10]. The concentration of regucalcin in the brain of cell signaling, protein synthesis, nuclear deoxyribonucleic acid and tissues of young rats is about 5x10-9 M [19]. Brain microsomal Ca2+- ribonucleic acid synthesis and cell proliferation and apoptosis, and ATPase activity was decreased with 10-9 M which is a physiological regulation of gene expression in various tissue and cell types [6,7]. concentration of regucalcin in the brain [10]. Meanwhile, regucalcin Regucalcin has been proposed to play a pivotal role as a suppressor plays a role as an activator in the regulation of the mitochondrial Ca2+ protein in signaling systems in maintaining of cell homeostasis [7]. The -ATPase activity of rat brain tissues [20]. The addition of regucalcin regucalcin gene is located on the X chromosome [8,9]. Interestingly, (10-10 to 10-8 M) into the enzyme reaction mixture containing calcium the map location for a growing number of diseases with a genetic chloride caused a significant increase in the mitochondrial Ca2+- basis is encompassed in human X chromosome, and these are known ATPase activity [20]. Thus, regucalcin may play a physiologic role to include syndromic and non-syndromic forms of X-linked mental in the regulation of intracellular Ca2+ homeostasis in rat brain. The retardation and X-linked neuromuscler diseases [9]. Regucalcin is concentration of regucalcin in the cerebral cortex and hippocampus expressed in rat brain neuron, and it is decreased in the cerebral of brain tissues is decreased with aging [19]. Suppressive effect of cortex and hippocampus of brain with aging [10,11]. There is growing regucalcin on brain microsomal Ca2+-ATPase activity has been found to evidence that regucalcin plays a pivotal role in brain neuronal cell weaken with aging [10]. Aging-induced elevation of brain microsomal regulation. Ca2+-ATPase activity may partly be resulted from an attenuation of the suppressive effect of regucalcin on the microsomal Ca2+-ATPase with Neuronal Ca2+ homeostasis and Ca2+ signaling regulate multiple aging, suggesting a pahophysiologic role of regucalcin in the regulation neuronal functions, including synaptic transmission, plasticity and of brain intracellular Ca2+ homeostasis. Many functional proteins are cell survival [12]. Ca2+-dependent biochemical processes have been degraded in the endoplasmic reticulum of brain neurons. Disturbance implicated in mechanisms of neuronal plasticity like long-term of Ca2+ homeostasis in the endoplasmic reticulum with aging may potentiation, which is likely to play an important role in learning and lead to an impairment of the degradation of modified proteins in memory [13]. These multiple functions of Ca2+ require fine regulation of brain neurons. The augmentation of modified proteins may promote its free intracellular concentration. Intracellular Ca2+ concentration in cytotoxicity in the neurons. the neuronal cells of brain is regulated by various buffering and transport systems such as the membrane Na+-Ca2+ exchanges, the membranous Ca2+/calmodulin-dependent protein kinases and protein kinase Ca2+-ATPase, Ca2+-binding proteins, and intracellular Ca2+ uptake C play an important role in response of the cells to calcium signal systems [14,15]. Ca2+ homeostasis undergoes subtle dysregulation in in various cell types [21]. These protein kinases play a pivotal role in the physiologic aging. Disturbance of brain Ca2+ homeostasis may play neuronal signaling processes [22]. Brain cytosolic Ca2+ -dependent a pivotal role in the causing of brain disease. Aging induces an increase protein kinase activity is raised with increasing age [23]. Regucalcin has in Ca2+ inflow by activating L-type voltage-sensitive Ca2+ channels been shown to have an inhibitory effect on Ca2+/calmodulin-dependent and a decrease in Ca2+ efflux due to inhibiting the plasma membrane protein kinase and protein kinase C activities in the cytoplasm of brain Ca2+-pumping activity (Ca2+-ATPase) in brain neurons, leading to a tissues [23] and neurons [24]. Suppressive effects of regucalcin on derangement of Ca2+ homeostasis [16]. Increased intracellular Ca2+ brain Ca2+-dependent protein kinase activity may be weakened with may be transported to the mitochondria and endoplasmic reticulum. increasing age [23]. Moreover, protein phosphatase plays an important In addition, the increase in the brain microsomal Ca2+-sequestrating role in intracellular signal transduction [25]. Regucalcin has been system (Ca2+-ATPase) with aging results in the microsomal calcium shown to have an inhibitory effect on Ca2+/calmodulin-dependent accumulation that is partly related to the brain toxicity by Ca2+. protein phosphatase activity toward phosphotyrosine, phosphoserine Intracellular Ca2+ signaling is fundamental to neuronal physiology and viability. Because of its ubiquitous roles, disruptions in Ca2+ homeostasis are implicated in diverse disease processes and have *Corresponding author: Masayoshi Yamaguchi, Department of Hematology and become a major focus of study in multifactorial neurodegenerative Medical Oncology, Emory University School of Medicine, 1365 C Clifton Road, NE, diseases such as Alzheimer’s disease [17]. The mitochondrial Ca2+- Atlanta, GA 30322, USA, Tel: 404-664-7422; E-mail: [email protected] ATPase activity and its calcium content are not altered with aging. The Received October 14, 2013; Accepted October 15, 2013; Published October 21, endoplasmic reticulum (microsomes) Ca2+-ATPase activity is found 2013 to increase with aging, and the microsomal calcium accumulation is Citation: Yamaguchi M (2013) Calcium Regulatory Protein, Regucalcin, may be induced [18]. This enhancement may be related to Ca2+-dependent a Key Molecule in Brain Disease. J Mol Genet Med 7: 87. doi: 10.4172/1747- factors in the cytoplasm of neuronal cells. Protein kinase C activity in 0862.1000087 the cytoplasm is increased with aging, and this enzyme may activate the Copyright: © 2013 Yamaguchi M. This is an open-access article distributed under 2+ 2+ the terms of the Creative Commons Attribution License, which permits unrestricted microsomal Ca -ATPase [18]. However, Ca -calmodulin dependent use, distribution, and reproduction in any medium, provided the original author and protein kinase may not be involved in aging-induced increase in the source are credited J Mol Genet Med ISSN: 1747-0862 JMGM, an open access journal Volume 7(4): 1000087 Citation: Yamaguchi M (2013) Calcium Regulatory Protein, Regucalcin, may be a Key Molecule in Brain Disease. J Mol Genet Med 7: 87. doi: 10.4172/1747-0862.1000087 Page 2 of 3 and phosphothreonine in rat brain cytoplasm and neurons [21,26]. ceruleus tissue of six pathologically confirmed Parkinson's disease Calbindin and S-100A proteins, which are Ca2+-binding protein in patients, and six age- and gender-matched non-neurological controls brain [11], have no effect on protein phosphatase activity in rat brain showed that several individual proteins are identified that have hitherto cytoplasm [26]. Regucalcin is localized in the microsomes of rat brain, not been associated with Parkinson's disease, such as regucalcin, which and aging causes a decrease in the microsomal regucalcin levels [27]. plays a role in maintaining intracellular Ca2+ homeostasis, and isoform Brain microsomal protein tyrosine phosphatase activity is increased 1 of kinectin, which is involved in transport of cellular components with increasing age [27]. This enzyme activity is found to be increased along microtubules [35]. In total 2495 proteins are identified, of in the presence of anti-regucalcin monoclonal antibody in the enzyme which 87 proteins were differentially expressed in the locus ceruleus reaction mixture, indicating that endogenous regucalcin in brain of Parkinson's disease patients compared with controls [35]. The microsomes may have a suppressive effect on the enzyme activity [27]. majority of these differentially expressed proteins are known to be The decrease in regucalcin in brain microsomes with aging is partly involved in processes that have been implicated in the pathogenesis related to the enhancement of microsomal protein tyrosine phosphatase of Parkinson's disease, including mitochondrial dysfunction, activity in the brain of aged rats. Interestingly, regucalcin has been found oxidative stress, protein misfolding, cytoskeleton dysregulation, and to be decreased in the nucleus of rat brain with aging [28]. Brain nuclear inflammation [14]. Moreover, the neurofibrillary