ory cells that carry out the auditory mechanotransduction pathway. In the mammalian OC, the hair cells are arranged in three rows of outer hair cells (OHC) and one of inner hair cell (IHC). Hair cells have protruding hair bundles and each hair bundle contains actin-filled stereocilia. Apically, the hair cells are covered by the tectorial membrane; basally, hair cells and various associated non-sensory cells referred to as supporting cells, sit on the basilar membrane. Oscillations in air pressure generated by sound waves are converted into fluid pressure that induce vibrations into the basilar membrane leading to deflections of the hair bundles, opening of mechanotransducer channels and cell depolarization. OHC serve as amplifiers while IHC transduce the auditory input. Specialized bipolar neurons known as spiral ganglion neuron (SGN) type I and II are the afferent connections of IHC (90-95% of SGN population) and OHC (remaining 5-10%), respectively; in turn, connecting to the brain. Specialized ribbon synapses are located at the pre-synaptic active zone of IHC and tethered by synaptic vesicles; upon stimulation they release glutamate. Slc17a8 known as Vglut3 is the IHC glutamate transporter. The molecular mechanisms of ribbon synapse function are not fully characterized yet. OHC are innervated by olivocochlear efferents originating from the superior olivary complex in the brainstem with an inhibitory effect. Each sterocilium in the hair bundle is connected to the next taller sterocilium neighbor via the tip link. The electron-dense areas at the insertion points of the tip link into the stereocilia are referred to as the lower tip-link density (LTLD) and upper tip-link density (UTLD), respectively. An elusive mechanotransduction (MET) channel - a non-selective cation channel with preference for calcium (Ca2+) and also potassium (K+) oscillates between open and closed states in the absence of stimuli; the molecular identity of the channel continues to be a conundrum. Stimuli that deflect the hair bundles of hair cells towards the tallest sterocilium result in the channel being open longer; if the tilt is towards the shortest, the channel closes. There are probably ~2 channels per stereocilium and they are located at the base of the tip link. The tip links consist of parallel cis-homodimers of cadherin 23 (Cdh23) interacting in trans with parallel protocadherin 15 (Pcdh15) cis-homodimers. Classical cadherins are characterized by the presence of five extracellular cadherin (EC) repeats; Cdh23 and Pcdh15 differ from the classical cadherins in that they contain 27 and 11 EC repeats, respectively. Adapters and myosin motors are associated with UTLD, LTLD and the stereocilium. The adapter Ush1c known as harmonin, is found in UTLD; it interacts with Myo7a and in vitro, with both Cdh23 and Pcdh15. Also, at UTLD is Myo1c which binds phosphatidylinositol 4,5-bisphosphate (PIP2) and in vitro, interacts with Cdh23. At LTLD there are Myo15a and the adapter Dfnb31, known as whirlin whose domain structure is similar to Ush1c/harmonin. Also at LTLD is Myo3a which interacts with the actin crosslinker espin (Espn). Ush1g known as Sans appears to reside at both LTLD and UTLD; structural studies indicate that Ush1c/harmonin and Ush1g/Sans can interact and the latter can also interact with Myo7a. The core of sterocilia has cross-linked and bundled actin filaments with a 2:1 ratio of gamma Actg1 to beta Actb, that are cross-linked by Espn, plastin 1 (Pls1) and t-Plastin (Pls3). At the base of stereocilia are Gpr98 known as Vlgr1 and Ush2a known as usherin. Myo6 is found in the cuticular plate to which the stereocilia are anchored; it interacts with otoferlin, a synaptic vesicle protein. Ptprq is also at the base of the stereocilium. How the tip links open the channels is not clear but models have been proposed and there are also models for the adaptation to mechanical stimuli that occurs on fast and slow timescale. More detailed functional characterization of proteins presented here and of others postulated to be implicated, is still to be delineated. Many of the proteins associated with the auditory mechanotransduction system have been implicated in hearing loss either non-syndromic or syndromic as in the case of Usher which also involves the blindness phenotype of retinitis pigmentosa (RP). To see the ontology report for annotations, Gviewer and download, click here...(less)