**6.2 Mechanotransduction**

The stereocilia of hair cells are the cellular organelle conducting mechanotransduction. The vibration of the basilar membrane and tectorial membrane or the motion of endolymphatic fluid induces the hair bundle deflection. When the deflection is toward the longest stereocilia (the positive or excitatory direction), the transduction channels are open. The influx of Ca2+ and K+ through the channels elicits changes of the membrane potential and glutamate release at the ribbon synapse in hair cells. When the hair bundle moves away from the longest stereocilia (the negative or inhibitory direction), the transduction channels close, and the membrane potential and transmitter release resume their resting statuses. Although the molecular machinery of mechanotransduction is not well understood, the 'gating spring' model is popular in the field. In this model, the tip link, whose axis is parallel to the direction of the mechanical sensitivity of the hair bundle, is thought as a sensor to the stretch of the hair bundle. Alternatively, an unknown structure attached to the tip link fulfills this function (Vollrath et al., 2007; Gillespie and Muller, 2009). The transduction channel was recently localized to the plasma membrane at the lower end of the tip link in the stereocilia (Beurg et al., 2008).

In mature hair cells, CDH23 (Siemens et al., 2004; Sollner et al., 2004) and PCDH15 (Ahmed et al., 2006) were found associated with the tip links. CDH23 is mainly at the upper part and PCDH15 at the lower part of the links (Kazmierczak et al., 2007; Alagramam et al., 2011). In *Cdh23V-2J* and *Pcdh15aw-6J* mice, the tip links are missing. Additionally, the response of the mechanotransduction is reduced. In the absence of stimulus, a fraction of transduction channels keep open in the wild-type hair cells, due to the resting tension of the tip links. However, the transduction channels in these two mutants do not open or take up the styryl dye FM1-43 at rest (Senften et al., 2006; Alagramam et al., 2011). Therefore, CDH23 and PCDH15 are believed to be components of the tip links and to participate in mechanotransduction in mature hair cells.

At the two ends of the tip link immediately beneath the stereocilia plasma membrane, there are electron-dense complexes, the UTLD and LTLD (Figure 4). Harmonin and MYO7A are present at the UTLD (Grillet et al., 2009; Michalski et al., 2009; Caberlotto et al., 2011; Grati and Kachar, 2011). In *Myo7a6J, Myo7a4626SB*, *Ush1cdfcr*, and *Ush1cdfcr-2J* mice, the adaptation of mechanotransduction, a process for the hair cells to recover their sensitivity under sustained mechanical stimulation, was found consistently abnormal, while the amplitude of mechanotransduction responses is sometimes normal (Kros et al., 2002; Grillet et al., 2009; Michalski et al., 2009). These results suggest that harmonin and MYO7A are involved in the transduction adaptation. SANS may exist at both the LTLD and UTLD (Caberlotto et al., 2011; Grati and Kachar, 2011). Its loss in hair cells (*Ush1g-/-*) causes elimination of the tip links and reduction in both the amplitude and sensitivity of the transduction currents (Caberlotto et al., 2011). In *Ush1gfl/fl Myo7a-cre+/-* mice, whose hair bundle morphology is intact, only the amplitude of transduction is affected. This finding indicates that SANS is implicated in mechanotransduction and plays a different role from harmonin or MYO7A.

*Gpr98* knockout and *Gpr98del7TM* mice also show defects in mechanotransduction, though there are some discrepancies between them (McGee et al., 2006; Michalski et al., 2007). In general, the sensitivity to the stimulation direction is changed in both outer and inner hair cells. The amplitude and sensitivity of the transduction current decrease in the outer hair cells, but are normal in the inner hair cells and the utricular hair cells. It is suggested that the misorganization of hair bundles in *Gpr98* mutant mice accounts of the abnormal sensitivity direction. Alternatively, GPR98 could be indirectly related with the cellular process of mechanotransduction.
