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RyR3-SOCE Mediates Salicylate-Induced [Ca2+]i Elevation in Spiral Ganglion Neurons by Activating ERK and JNK Signaling Pathways
Vol 37, Issue 8, 2023
Abstract
Background: Sodium salicylate (SS) is known to cause injury to spiral ganglion neurons (SGN) through excitatory toxicity and calcium overload. Store-operated Ca2+ entry (SOCE) has been identified as a mediator of Ca2+ influx that can cause damage to various neurons, including SGN. This study aimed to investigate the role of SOCE and downstream molecules of extracellular signal-regulated protein kinases (ERK) and c-Jun N-terminal kinase (JNK) pathways in the process of SS-induced elevation of intracellular calcium concentration ([Ca2+]i) in SGN. Methods: The expressions of ryanodine receptor 3 (RyR3), Orai calcium release-activated calcium channel 1 (Orai1) and Stromal interaction molecule 1 (Stim1) were tested on rat cochlear SGN cultured in vitro using immunofluorescence. The SGN were then exposed to SS, RyR agonist (caffeine), RyR antagonist (dantrolene), Orai1 antagonist (MRS1845), ERK and JNK phosphorylation inhibitor (1,4-Diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126)/5-[(5-Nitro-1,3-thiazol-2-yl)thio]-1,3,4-thiadiazol-2-amine (SU3327)). Intracellular calcium imaging, FqPCR and Western blotting were used to detect [Ca2+]i, mRNA and protein expressions of RyR3, Orai1, Stim1 and molecules of ERK and JNK pathways. Results: After 3 and 6 h of SS treatment, there was a significant increase in SGN [Ca2+]i, as well as significant upregulations of mRNA and proteins of RyR3, Stim1, and Orai1. Inhibition of RyR or Orai1 reversed these effects of SS. Additionally, SS led to enhanced phosphorylation of ERK and JNK in SGN, accompanied by increased expression of their downstream transcription factors ETS-like 1 transcription factor 1 (Elk-1), early growth response 1 (Egr-1), and v-jun avian sarcona virus 17 oncogene homolog (c-Jun). Furthermore, activation of RyR promoted ERK and JNK phosphorylation, and inhibition of ERK and JNK reduced the upregulation of RyR3, Stim1, and Orai1 expressions caused by SS. Conclusions: SS may enhance RyR3-SOCE and activate ERK and JNK signaling, leading to [Ca2+]i elevation in SGN.
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Copyright (c) 2023 Huiying Chen, Xiaoyu Lin, Jialin Huang, Xiaoting Zhu, Jinlan Liu, Jinxia Chen, Jianqi Yi, Wanli Ye, Wenfeng Xu, Jiping Su
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy