Salicylate-Induced Ototoxicity of Spiral Ganglion Neurons: Ca 2+ /CaMKII-Mediated Interaction Between NMDA Receptor and GABA A Receptor

Abstract

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_AR) in rat cochlear spiral ganglion neurons (SGNs). After treatment with SS, NMDA, and an NMDAR inhibitor (APV), the changes of GABA_AR β3 (GABR β3) mRNA, surface and total protein, and GABA_AR currents in SGNs were assessed by quantitative PCR, Western blot, and whole-cell patch clamp. Mechanistically, SS and/or NMDA increased the GABR β3 mRNA expression, while decreased GABR β3 surface protein levels and GABA_AR-mediated currents. Moreover, application of SS and/or NMDA showed promotion in phosphorylation levels at S383 of GABR β3. Collectively, Ca²⁺ chelator (BAPTA) or Ca²⁺/CaMKII inhibitor (KN-93) reversed the effects of SS and/or NMDA on GABA_AR. Therefore, we hypothesize that the interaction between NMDAR and GABA_AR 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.

https://ift.tt/2H8Jg6L