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Putting the Pieces Together: the Hair Cell Transduction Complex

Abstract

Identification of the components of the mechanosensory transduction complex in hair cells has been a major research interest for many auditory and vestibular scientists and has attracted attention from outside the field. The past two decades have witnessed a number of significant advances with emergence of compelling evidence implicating at least a dozen distinct molecular components of the transduction machinery. Yet, how the pieces of this ensemble fit together and function in harmony to enable the senses of hearing and balance has not been clarified. The goal of this review is to summarize a 2021 symposium presented at the annual mid-winter meeting of the Association for Research in Otolaryngology. The symposium brought together the latest insights from within and beyond the field to examine individual components of the transduction complex and how these elements interact at molecular, structural, and biophysical levels to gate mechanosensitive channels and initiate sensory transduction in the inner ear. The review includes a brief historical background to set the stage for topics to follow that focus on structure, properties, and interactions of proteins such as CDH23, PCDH15, LHFPL5, TMIE, TMC1/2, and CIB2/3. We aim to present the diversity of ideas in this field and highlight emerging theories and concepts. This review will not only provide readers with a deeper appreciation of the components of the transduction apparatus and how they function together, but also bring to light areas of broad agreement, areas of scientific controversy, and opportunities for future scientific discovery.

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Acknowledgements

M.T. is an alumnus of the Frontiers in Life Science PhD program of Université Paris Diderot and thanks the Fondation Agir pour l’Audition for a doctoral fellowship. E.G. is an investigator of the Howard Hughes Medical Institute.

Funding

This work was supported by NIH/NIDCD grant R01-DC013521 (J.R.H.), by the French National Agency for Research (ANR-11-BSV5 0011 and ANR-16-CE13-0015) and the Labex Celti-sphybio ANR-10-LABX-0038 (M.T.). A.B. was supported by the Intramural Research Program number NS002945 of the NINDS, NIH, Bethesda, MD, to Kenton J. Swartz. T.N. was supported by NIH/NIDCD grants R01-DC013572 and R01-DC013531.

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Correspondence to Jeffrey R. Holt.

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J.R.H. holds patents on TMC1 gene therapy and is an advisor to several biotech firms focused on inner-ear therapies. The authors report no other conflicts.

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Holt, J.R., Tobin, M., Elferich, J. et al. Putting the Pieces Together: the Hair Cell Transduction Complex. JARO 22, 601–608 (2021). https://doi.org/10.1007/s10162-021-00808-0

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Keywords

  • hair cell
  • sensory transduction
  • mechanotransduction
  • mechanosensory transduction
  • TMC1
  • TMC2
  • TMIE
  • TMHS
  • LHFPL5
  • PCDH15
  • CDH23
  • CIB2
  • CIB3
  • TOMPT
  • tip link
  • transduction channel