title: Noise-induced cochlear F-actin depolymerization is mediated via ROCK2/p-ERM signaling.
abstract: Our previous work has suggested that traumatic noise activates Rho-GTPase pathways in cochlear outer hair cells (OHCs), resulting in cell death and noise-induced hearing loss (NIHL). In this study, we investigated Rho effectors, Rho-associated kinases (ROCKs), and the targets of ROCKs, the ezrin-radixin-moesin (ERM) proteins, in the regulation of the cochlear actin cytoskeleton using adult CBA/J mice under conditions of noise-induced temporary threshold shift (TTS) and permanent threshold shift (PTS) hearing loss, which result in changes to the F/G-actin ratio. The levels of cochlear ROCK2 and p-ERM decreased 1 h after either TTS- or PTS-noise exposure. In contrast, ROCK2 and p-ERM in OHCs decreased only after PTS-, not after TTS-noise exposure. Treatment with lysophosphatidic acid, an activator of the Rho pathway, resulted in significant reversal of the F/G-actin ratio changes caused by noise exposure and attenuated OHC death and NIHL. Conversely, the down-regulation of ROCK2 by pretreatment with ROCK2 siRNA reduced the expression of ROCK2 and p-ERM in OHCs, exacerbated TTS to PTS, and worsened OHC loss. Additionally, pretreatment with siRNA against radixin, an ERM protein, aggravated TTS to PTS. Our results indicate that a ROCK2-mediated ERM-phosphorylation signaling cascade modulates noise-induced hair cell loss and NIHL by targeting the cytoskeleton. We propose the following cascade following noise trauma leading to alteration of the F-actin arrangement in the outer hair cell cytoskeleton: Noise exposure reduces the levels of GTP-RhoA and subsequently diminishes levels of RhoA effector ROCK2 (Rho-associated kinase 2). Phosphorylation of ezrin-radixin-moesin (ERM) by ROCK2 normally allows ERM to cross-link actin filaments with the plasma membrane. Noise-decreased levels of ROCK results in reduction of phosphorylation of ERM that leads to depolymerization of actin filaments. Lysophosphatidic acid (LPA), an agonist of RhoA, binds to the G-protein-coupled receptor (GPCR) leading to activation of RhoA through Gα12/13 and RhoGEF. Administration of LPA rescues the noise-diminished F/G-actin ratio.
authors: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Yu
authors: Y
authors: Han
authors: Xianren
authors: X
authors: Wang
authors: Jun
authors: J
authors: Chen
authors: Su-Hua
authors: SH
authors: Sha
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003051:Cochlea / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016057:Evoked Potentials, Auditory, Brain Stem; D020868:Gene Silencing / Q000187:drug effects; D018072:Hair Cells, Auditory, Outer / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008808:Mice, Inbred CBA; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D054460:rho-Associated Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C513242:Etv5 protein, mouse; D008246:Lysophospholipids; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C071776:radixin; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; C032881:lysophosphatidic acid
keywords: ROCK2 siRNA; actin cytoskeleton; noise-induced hearing loss; radixin siRNA; rho-associated kinases