The molecules that mediate sensory transduction in the mammalian inner ear

Abstract

Years of searching and researching have finally yielded a few leads in the quest to identify molecules required for mechanosensory transduction in the mammalian inner ear. Studies of human and mouse genetics have raised the profile of several molecules that are crucial for the function sensory hair cells. Follow up studies have begun to define the molecular function and biochemical interactions of several key proteins. These studies have exposed a sensory transduction apparatus that is more complex than originally envisioned and have reinvigorated the search for additional molecular components required for normal inner ear function.

Figure 1

Scanning electron micrographs of hair bundles from the rodent inner ear. (a) Hair bundle from a P15 rat inner hair cell. Scale bar = 2 µm. Reprinted from Beurg et al. (2006). (b) Hair bundle from a mouse hair outer cell. Scale bar = 2 µm. Reprinted with permission from David Furness. (c) Hair bundle from a mouse vestibular hair cell. Scale bar = 2 µm. Reprinted from Holt et al. (2002).

Figure 2

Schematic diagrams of the mechanosensory hair bundle of the mammalian inner ear. (a) Hair bundles are comprised of 50–100 modified microvilli, known as stereocilia (pictured in green). They are arranged in a stair case pattern of increasing height. At the tall edge is a single true cilium, known as the kinocilium which is present in vestibular hair bundles and auditory bundles during development. Stereocilia are held together in a compact bundle by extracelluar linkages know as ankle links and horizontal top connectors. The bundle is anchored to the cuticular plate at the apical surface of the hair cell cell-body. Deflection of the hair bundle toward the kinocilium is excitatory. The region within the red box is enlarged at the right to show greater detail. (b) Stereocilia have cores of actin filaments crosslinked with Espin and Fimbrin. Several unconventional myosins, shuttle cargo up and down the stereocilia, function to maintain bundle lingages and hold the cell membrane in place around the actin core. Four key components of the biophysically-defined model for hair cell sensory transduction are shown here: the gating spring, the mechanosensitive channel, the tip-link and the adaptation motor. Modified from Géléoc and Holt (2014). The molecular composition of the hair cell sensory transduction apparatus is under investigation.

Figure 3

Three possible configurations of TMC1 and TMC2 within the sensory transduction channel complex. Modified from Kawashima et al. (2014). (a) TMC1/TMC2 may be linker proteins that bind PCDH15 and convey tension to pore-forming subunits of the transduction channel. In this configuration, extracellular domains of TMC1/TMC2 may be within close enough proximity to the mouth of the pore to modify calcium-selectivity and single-channel conductance. (b) TMC1/TMC2 may be essential components of the channel linking directly with PCDH15. In this case, TMC1/TMC2 are part of an ion channel complex that includes other, as yet unknown, ion channel subunits. (c) In this scenario, TMC1/TMC2 are pore-forming subunits of the transduction channel and are coupled directly PCDH15. Modified from Kawashima et al. (2014). (d) A model based on the most recent biochemical data which suggest interactions between PCDH15 and TMC1 (Maeda et al., 2014), PCDH15 and TMIE (Zhao et al., 2014), PCDH15 and TMHS and shows that TMHS is necessary for TMC1 localization at the tips of sterocilia (Beurg et al., 2015).