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.

Conditional deletion of pejvakin in adult outer hair cells causes progressive hearing loss in mice

“…Based on our finding that inactivation of pejvakin in adult OHCs leads to progressive hearing loss, it is tempting to speculate that milder alleles of pejvakin may cause a slow degeneration of OHCs in adults while leaving hair cell development unaffected. Further, we show that pejvakin forms protein complexes with Rho effectors, including ROCK2, which has been implicated in the regulation of actin dynamics in OHCs (Kalinec et al, 2000; Zhang et al, 2003; Han et al, 2015). Understanding the effects of individual pejvakin mutations on Rho signaling may therefore shed light on the pathogenetic mechanisms that underlie the observed variability in clinical phenotypes in DFNB59 patients.…”

The receptor tyrosine kinase EPHB6 regulates catecholamine exocytosis in adrenal gland chromaffin cells

“…It, on the other hand, might have a direct default negative effect on RHOA activation, which promotes F-actin stabilization typically. ROCK/Ezrin (49) and ROCK/LIMK/Cofilin (50) pathways are known to be downstream of RHOA, although the latter is not activated in ACh-stimulated AGCCs (data not shown). Factin depolymerization is not only essential in moving the slow-release CAT-containing vesicles to the docking position (51) but is also critical for optimal vesicular fusion and sewage of CAT content from the vesicles in the IRV pool during rapid exocytosis.…”

Altered protein quality control contributes to noise-induced hearing loss

“…Cytoskeletal proteins enriched in HCs have been widely studied in hearing research predominantly due to their important functions in HC stereocilia structure, cytoskeletal networks, and contractility of outer HCs (40-42). Increased levels of these proteins may suggest moderate to high levels of noise disrupt protein-protein interactions or drive a rapid reorganization of cytoskeletal protein complexes especially F-actin and myosin that were previously shown to have prompt responses within 10 min after calcium deprivation in cochlea (43) However, the degree of structural protein alterations may depend on multiple factors including the level and duration of exposure, for example, extended noise exposure induces actin depolymerization (44). Tubulin proteins are highly abundant in neurons and had increased levels after noise exposure.…”