Functional decreases in P2X7 receptors are associated with retinoic acid-induced neuronal differentiation of Neuro-2a neuroblastoma cells |
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| Authors: | Pei-Yu Wu Yu-Chia Lin Chia-Ling Chang Hsing-Tsen Lu Chia-Hsuan Chin Tsan-Ting Hsu Dachen Chu Synthia H Sun |
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| Institution: | 1. Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan, ROC;2. Department of Neurosurgery in Hoping Branch, Taipei, Taiwan, ROC;3. Department of Education and Research, Taipei City Hospital, Taiwan, ROC;1. Nanoscopy & NIC@IIT, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy;2. Dipartimento di Informatica, Bioingegneria, Robotica e Ingegneria dei Sistemi, (DIBRIS), Università degli Studi di Genova, Via All’Opera Pia 13, 16145 Genova, Italy;3. Materials Characterization Facility, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy;4. Nanophysics Department, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy;1. Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, 465 Kajiicho Kamigyo-ward, Kyoto 602-8566, Japan;2. Department of Bio-Ionomics, Kyoto Prefectural University of Medicine, 465 Kajiicho Kamigyo-ward, Kyoto 602-8566, Japan;1. Department of Chemical Engineering, Indian Institute of Technology, Kanpur 208016, U.P., India;2. Department of Materials Science and Engineering, Indian Institute of Technology, Kanpur 208016, U.P., India;3. Materials Research Center, Indian Institute of Science, Bangalore 560012, Karnataka, India;1. Department of Marine Ecology, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China;2. Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Ministry of Education, Pharmacology Department, School of Pharmacy, Shihezi University, Shihezi 832002, China;3. From the Departments of Neuropsychopharmacology and Hospital Pharmacy and Nagoya University Graduate School of Medicine, 466-8560, Nagoya, Japan;4. Cell Pharmacology, Nagoya University Graduate School of Medicine, 466-8560, Nagoya, Japan;5. the F. M. Kirby Neurobiology Center, Children''s Hospital, and Departments of Neurology and Neurobiology, Harvard Medical School, Boston, Massachusetts 02115 |
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| Abstract: | Neuro-2a (N2a) cells are derived from spontaneous neuroblastoma of mouse and capable to differentiate into neuronal-like cells. Recently, P2X7 receptor has been shown to sustain growth of human neuroblastoma cells but its role during neuronal differentiation remains unexamined. We characterized the role of P2X7 receptors in the retinoic acid (RA)-differentiated N2a cells. RA induced N2a cells differentiation into neurite bearing and neuronal specific proteins, microtubule-associated protein 2 (MAP2) and neuronal specific nuclear protein (NeuN), expressing neuronal-like cells. Interestingly, the RA-induced neuronal differentiation was associated with decreases in the expression and function of P2X7 receptors. Functional inhibition of P2X7 receptors by P2X7 receptor selective antagonists, 5′-triphosphate, periodate-oxidized 2′,3′-dialdehyde ATP (oATP), brilliant blue G (BBG) or A438079 induced neurite outgrowth. In addition, RA and oATP treatment stimulated the expression of neuron-specific class III beta-tubulin (TuJ1), and knockdown of P2X7 receptor expression by siRNA induced neurite outgrowth. To elucidate the possible mechanism, we found the levels of basal intracellular Ca2+ concentrations (Ca2+]i) were decreased in either RA- or oATP-differentiated or P2X7 receptor knockdown N2a cells. Simply cultured N2a cells in low Ca2+ medium induced a 2-fold increase in neurite length. Treatment of N2a cells with ATP hydrolase apyrase and the P2X7 receptors selective antagonist oATP or BBG decreased cell viability and cell number. Nevertheless, oATP but not BBG decreased cell proliferation and cell cycle progression. These results suggest for the first time that decreases in expression/function of P2X7 receptors are involved in neuronal differentiation. We provide additional evidence shown that the ATP release-activated P2X7 receptor is important in maintaining cell survival of N2a neuroblastoma cells. |
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