Abstract
Extracellular signal-regulated kinase (ERK) is a member of the family of mitogen-activated protein kinases (MAPKs) and coordinately regulates a multitude of cellular processes. In response to a variety of extracellular stimuli, phosphorylation of both threonine and tyrosine residues activates ERK. Recent evidence indicates that ERK is activated in response to cellular stress such as acoustic trauma. However, the specific role of ERK isoforms in auditory function is not fully understood. Here, we show that the isoform ERK2 plays an important role in regulating hair cell (HC) survival and noise-induced hearing loss (NIHL) in mice (C57BL/6J). We found that conditional knockout mice deficient for Erk2 in the inner ear HCs had hearing comparable to control mice and exhibited no HC loss under normal conditions. However, we found that these knockout mice were more vulnerable to noise and had blunted recovery from NIHL compared to control mice. Furthermore, we observed a significantly lower survival rate of inner hair cells in these mice compared to control mice. Our results indicate that ERK2 plays important roles in the survival of HC in NIHL.
Highlights
Some reports have suggested that isoforms of ERK, ERK1, and ERK2 may play distinct roles in some conditions, these isoforms share 84% of amino acid identity and have a very similar substrate profile[15]
We found that auditory thresholds of HC-E2CKO mice were significantly increased compared to control mice after noise exposure, suggesting that ERK2 plays an important role in protecting the inner ear from noise exposure
Similar to the above study, we observed that 5 h after noise exposure, phosphorylation levels of ERK1 and ERK2 were increased in the modiolus (MO), lateral wall tissue (LW), and neurosensory epithelium (NSE) (Fig. 1a,b) (n = 4 for each group)
Summary
Some reports have suggested that isoforms of ERK, ERK1, and ERK2 may play distinct roles in some conditions, these isoforms share 84% of amino acid identity and have a very similar substrate profile[15]. Since ERK1 and ERK2 are both activated by MEK, inhibiting MEK will inhibit both ERKs, rendering it difficult to ascribe each isoform a unique physiological function. To circumvent this issue, we examined the role of ERK2 in the cochlea using HC-specific Erk[2] conditional knockout mice (hereafter referred to as HC-E2CKO). We found that auditory thresholds of HC-E2CKO mice were significantly increased compared to control mice after noise exposure, suggesting that ERK2 plays an important role in protecting the inner ear from noise exposure. In response to acoustic trauma, ERK2 plays an important role in mediating the survival of IHCs and synaptic ribbons
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