Salicylate-Induced Ototoxicity of Spiral Ganglion Neurons: Ca2+/CaMKII-Mediated Interaction Between NMDA Receptor and GABAA Receptor
Salicylate-Induced Ototoxicity of Spiral Ganglion Neurons: Ca2+/CaMKII-Mediated Interaction Between NMDA Receptor and GABAA Receptor
复制标题
水杨酸盐诱导的螺旋神经节神经元耳毒性：Ca2/CaMKII 介导的 NMDA 受体与 GABA(A) 受体之间的相互作用
DOI：
10.1007/s12640-019-0006-8
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发表时间：
2019-05-01
影响因子：
3.7
通讯作者：
Su, Jiping
中科院分区：
文献类型：
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作者：
Qin, Danxue;Liu, Peiqiang;Su, Jiping
水杨酸钠（SS）是一种非甾体抗炎药，在临床实践中广泛应用。因此，我们旨在研究水杨酸钠潜在的耳毒性机制：Ca²⁺/钙调蛋白依赖性蛋白激酶II（Ca²⁺/CaMKII）在大鼠耳蜗螺旋神经节神经元（SGNs）中N - 甲基 - D - 天冬氨酸受体（NMDAR）和γ - 氨基丁酸A受体（GABA(A)R）相互作用中的影响。在用SS、NMDA和一种NMDAR抑制剂（APV）处理后，通过定量PCR、蛋白质印迹和全细胞膜片钳评估SGNs中GABA(A)Rβ3（GABRβ3）mRNA、表面和总蛋白以及GABA(A)R电流的变化。从机制上讲，SS和/或NMDA增加了GABRβ3 mRNA的表达，同时降低了GABRβ3表面蛋白水平和GABA(A)R介导的电流。此外，应用SS和/或NMDA显示GABRβ3的S383磷酸化水平升高。总体而言，Ca²⁺螯合剂（BAPTA）或Ca²⁺/CaMKII抑制剂（KN - 93）逆转了SS和/或NMDA对GABA(A)R的作用。因此，我们假设NMDAR和GABA(A)R之间的相互作用参与了SS诱导的SGNs损伤。此外，潜在的分子机制与Ca²⁺/CaMKII介导的信号通路有关，这表明钙信号调节受体之间的相互作用介导了SS的耳毒性。
Sodium salicylate (SS) is one of the nonsteroidal anti-inflammatory drugs and widely used in clinical practice. Therefore, we aimed to investigate the potential ototoxicity mechanism of sodium salicylate: the influence of Ca2+/calmodulin-dependent protein kinase II (Ca2+/CaMKII) in interaction between NMDA receptors (NMDAR) and GABA(A) receptors (GABA(A)R) in rat cochlear spiral ganglion neurons (SGNs). After treatment with SS, NMDA, and an NMDAR inhibitor (APV), the changes of GABA(A)R beta 3 (GABR beta 3) mRNA, surface and total protein, and GABA(A)R currents in SGNs were assessed by quantitative PCR, Western blot, and whole-cell patch clamp. Mechanistically, SS and/or NMDA increased the GABR beta 3 mRNA expression, while decreased GABR beta 3 surface protein levels and GABA(A)R-mediated currents. Moreover, application of SS and/or NMDA showed promotion in phosphorylation levels at S383 of GABR beta 3. Collectively, Ca2+ chelator (BAPTA) or Ca2+/CaMKII inhibitor (KN-93) reversed the effects of SS and/or NMDA on GABA(A)R. Therefore, we hypothesize that the interaction between NMDAR and GABA(A)R is involved in the SGNs damage induced by SS. In addition, the underlying molecular mechanism is related to Ca2+/CaMKII-mediated signaling pathway, which suggests that the interaction between calcium signal-regulated receptors mediates SS ototoxicity.