Noise‐induced cochlear F‐actin depolymerization is mediated via ROCK2/p‐ERM signaling

• Published in: Journal of neurochemistry Vol. 133; no. 5; pp. 617 - 628
• Main Authors: Han, Yu, Wang, Xianren, Chen, Jun, Sha, Su‐Hua
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2015
• Subjects: actin cytoskeleton; Actins - genetics; Actins - metabolism; Animals; Cochlea - injuries; Cochlea - metabolism; Cochlea - pathology; Cytoskeletal Proteins - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Evoked Potentials, Auditory, Brain Stem; Gene Silencing - drug effects; Hair Cells, Auditory, Outer - pathology; Hearing loss; Hearing Loss, Noise-Induced - metabolism; Hearing Loss, Noise-Induced - pathology; Kinases; Lysophospholipids - pharmacology; Male; Membrane Proteins - genetics; Mice; Mice, Inbred CBA; Neurochemistry; noise‐induced hearing loss; Polymerization; radixin siRNA; rho-Associated Kinases - genetics; rho-Associated Kinases - physiology; rho‐associated kinases; RNA, Small Interfering - pharmacology; ROCK2 siRNA; Signal Transduction - genetics; Signal Transduction - physiology; Transcription Factors - genetics; Transcription Factors - physiology; actin cytoskeleton; ROCK2 siRNA; noise-induced hearing loss; rho-associated kinases; radixin siRNA
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13061

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. 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.