title: Interleukin-6 reduces NMDAR-mediated cytosolic Ca²⁺ overload and neuronal death via JAK/CaN signaling.
abstract: Cytosolic Ca(2+) overload induced by N-methyl-D-aspartate (NMDA) is one of the major causes for neuronal cell death during cerebral ischemic insult and neurodegenerative disorders. Previously, we have reported that the cytokine interleukin-6 (IL-6) reduces NMDA-induced cytosolic Ca(2+) overload by inhibiting both L-type voltage-gated calcium channel (L-VGCC) activity and intracellular Ca(2+) store release in cultured cerebellar granule neurons (CGNs). Here we aimed to show that NMDA-gated receptor channels (i.e., NMDA receptors, NMDARs) are an inhibitory target of IL-6 via a mediation of calcineurin (CaN) signaling. As expected, IL-6 decreased NMDAR-mediated cytosolic Ca(2+) overload and inward current in cultured CGNs. The NMDAR subunits, NR1, NR2A, NR2B and NR2C, were expressed in CGNs. Blocking either of NR2A, NR2B and NR2C with respective antagonist reduced NMDA-induced extracellular Ca(2+) influx and neuronal death. Importantly, the reduced percentages in extracellular Ca(2+) influx and neuronal death by either NR2B or NR2C antagonist were weaker in the presence of IL-6 than in the absence of IL-6, while the reduced percentage by NR2A antagonist was not significantly different between the presence and the absence of IL-6. AG490, an inhibitor of Janus kinase (JAK), abolished IL-6 protection against extracellular Ca(2+) influx, mitochondrial membrane depolarization, neuronal death, and CaN activity impairment induced by NMDA. The CaN inhibitor FK506 reduced these IL-6 neuroprotective properties. Collectively, these results suggest that IL-6 exerts neuroprotection by inhibiting activities of the NMDAR subunits NR2B and NR2C (but not NR2A) via the intermediation of JAK/CaN signaling.
authors.affiliation: Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province 226001, China.
authors.forename: Song-Hua
authors.initials: SH
authors.lastname: Ma
authors.affiliation: Department of Biological Science and Technology and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Mailbox 426, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Qian-Xing
authors.initials: QX
authors.lastname: Zhuang
authors.affiliation: Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province 226001, China.
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Shen
authors.affiliation: Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province 226001, China. Electronic address: yppeng@ntu.edu.cn.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Peng
authors.affiliation: Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province 226001, China. Electronic address: yhqiu@ntu.edu.cn.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Qiu
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051580:Neuronal Calcium-Sensor Proteins / Q000378:metabolism*; D000066829:Neuroprotection; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D015850:Interleukin-6; D051580:Neuronal Calcium-Sensor Proteins; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; D019703:Calcineurin; D002118:Calcium
keywords: Calcineurin; Cytosolic Ca(2+) overload; Interleukin-6; NMDA receptor subunits; Neuroprotection