Traumatic-noise-induced hair cell death and hearing loss is mediated by activation of CaMKKβ

Cell Mol Life Sci. 2022 Apr 19;79(5):249. doi: 10.1007/s00018-022-04268-4.


Background: The Ca2+/calmodulin-dependent protein kinase kinases (CaMKKs) are serine/threonine-directed protein kinases that are activated following increases in intracellular calcium, playing a critical role in neuronal signaling. Inner-ear-trauma-induced calcium overload in sensory hair cells has been well documented in the pathogenesis of traumatic noise-induced hair cell death and hearing loss, but there are no established pharmaceutical therapies available due to a lack of specific therapeutic targets. In this study, we investigated the activation of CaMKKβ in the inner ear after traumatic noise exposure and assessed the prevention of noise-induced hearing loss (NIHL) with RNA silencing.

Results: Treatment with short hairpin RNA of CaMKKβ (shCaMKKβ) via adeno-associated virus transduction significantly knocked down CaMKKβ expression in the inner ear. Knockdown of CaMKKβ significantly attenuated noise-induced hair cell loss and hearing loss (NIHL). Additionally, pretreatment with naked CaMKKβ small interfering RNA (siCaMKKβ) attenuated noise-induced losses of inner hair cell synapses and OHCs and NIHL. Furthermore, traumatic noise exposure activates CaMKKβ in OHCs as demonstrated by immunolabeling for p-CaMKI. CaMKKβ mRNA assessed by fluorescence in-situ hybridization and immunolabeling for CaMKKβ in OHCs also increased after the exposure. Finally, pretreatment with siCaMKKβ diminished noise-induced activation of AMPKα in OHCs.

Conclusions: These findings demonstrate that traumatic-noise-induced OHC loss and hearing loss occur primarily via activation of CaMKKβ. Targeting CaMKKβ is a key strategy for prevention of noise-induced hearing loss. Furthermore, our data suggest that noise-induced activation of AMPKα in OHCs occurs via the CaMKKβ pathway.

Keywords: Activation of CaMKKβ after traumatic noise exposure; Adeno-associated virus-mediated gene silencing; Fluorescence in-situ hybridization in adult mouse cochleae; Prevention of noise-induced hearing loss by RNA silencing in-vivo.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
  • Cell Death
  • Deafness* / metabolism
  • Hair / metabolism
  • Hair Cells, Auditory, Outer / metabolism
  • Hair Cells, Auditory, Outer / pathology
  • Hearing Loss, Noise-Induced* / etiology
  • Hearing Loss, Noise-Induced* / pathology
  • Hearing Loss, Noise-Induced* / prevention & control
  • Humans
  • Protein Serine-Threonine Kinases
  • RNA, Small Interfering / metabolism


  • RNA, Small Interfering
  • Protein Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • AMP-Activated Protein Kinases
  • Calcium