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.

Keywords: CDH23; CIB2; CIB3; LHFPL5; PCDH15; TMC1; TMC2; TMHS; TMIE; TOMPT; hair cell; mechanosensory transduction; mechanotransduction; sensory transduction; tip link; transduction channel.

Fig. 1

Structure of the PCDH15/LHFPL5 complex at the bottom of the mammalian tip link. It remains unclear how this structure couples to TMCs (modeled here using the structure of TMEM16A) and the actin cytoskeleton

Fig. 2

Mutation of residues in the TMC1 cavity alters the mechanosensory transduction channel properties. a Ribbon representation of the murine TMC1 model based on the nhTMEM16 structure. One protomer is colored in yellow, and the other in gray. The transmembrane segments are numbered, and the intracellular (IC) and extracellular (EC) sides are indicated. The approximated location of the lipid carbonyls of the plasma membrane as calculated by the PPM server is represented with two planes of gray spheres. b Surface representation of the TMC1 cavity formed by TM4–TM7 depicting deafness-causing mutations that alter MT channel properties in magenta (M412K, T416K, D528N, D569N, W554L), cysteine mutants altering channel properties after treatment with a water-soluble cysteine cross-linker reagent (MTSET) in yellow (N404, S408, G411, I440, T531, T532, T535), and cysteine cross-linking mutants with no effect on MT after MTSET treatment in green (D419, S571, I570, N573, V574, G596)

Fig. 3

Cross-sectional view of the transmembrane domains of the mechanosensory transduction components in zebrafish stereocilia. The TEM micrograph shows a typical tip link and upper insertion plaque in two neighboring stereocilia in a zebrafish hair cell. The two independently trafficking protein complexes (i) Pcdh15a and the Lhfpl5a/b proteins and the (ii) Tmc/Tmie complex are indicated, along with the Golgi protein Tomt, which is critical for trafficking of the Tmc1/2 proteins to the hair bundle. Ten transmembrane domains are predicted for the Tmcs based on homology to Tmem16a channels (see sections above). The transmembrane domain of Pcdh15a, including internal and external residues, physically interacts with the N termini of the Tmc proteins (dashed arrow)