id: PW:0001503
rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0001503
title: auditory mechanotransduction pathway
description: The auditory system has exquisitely intricate mechanisms that convert mechanical stimuli
  - mechanotransduction, intro electrical signals that are processed by the brain and account for the
  perception of sound, gravity and movement. The inner ear - a fluid-filled organ, contains the shell-shaped
  cochlea and the vestibule responsible for sound and for gravitation and movement mechanotransduction,
  respectively. Within the cochlea, the organ of Corti (OC) contains the hair cells - specialized sensory
  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).
diagram_image: https://rgd.mcw.edu/pathway/PW0001503/auditory%20mechanotransduction%20pathway/pwmap.png
pathway_studio_file: https://rgd.mcw.edu/pathway/PW0001503/auditory%20mechanotransduction%20pathway/auditory%20mechanotransduction%20pathway.gpp
diagram_pathway_links: []
diagram_gene_links:
- id: RGD:628837
  label: Actb
- id: RGD:1304556
  label: Actg1
- id: RGD:619760
  label: Cdh23
- id: RGD:631330
  label: Dfnb31
- id: RGD:620652
  label: Espn
- id: RGD:1562101
  label: Gpr98
- id: RGD:1561873
  label: Myo15a
- id: RGD:620443
  label: Myo1c
- id: RGD:1560083
  label: Myo3a
- id: RGD:1560646
  label: Myo6
- id: RGD:628830
  label: Myo7a
- id: RGD:620646
  label: Otof
- id: RGD:1590969
  label: Pcdh15
- id: RGD:1307142
  label: Pls1
- id: RGD:621409
  label: Pls3
- id: RGD:620779
  label: Ptprq
- id: RGD:628870
  label: Slc17a8
- id: RGD:1303329
  label: Ush1c
- id: RGD:1304551
  label: Ush1g
- id: RGD:628777
  label: Ush2a
diagram_chemicals:
- id: CHEBI:29108
  label: Ca2+
- id: PUBCHEM.COMPOUND:33032
  label: glutamate
- id: CHEBI:26217
  label: K+
diagram_edges:
- source: Cdh23
  relation: associated_with
  target: Myo1c
- source: Cdh23
  relation: associated_with
  target: Pcdh15
- source: Cdh23
  relation: associated_with
  target: Ush1c
- source: Espn
  relation: associated_with
  target: Myo3a
- source: Myo1c
  relation: associated_with
  target: PIP2
- source: Myo6
  relation: associated_with
  target: Otof
- source: Myo7a
  relation: associated_with
  target: Ush1c
- source: Myo7a
  relation: associated_with
  target: Ush1g
- source: Pcdh15
  relation: associated_with
  target: Ush1c
- source: Ush1c
  relation: associated_with
  target: Ush1g
- source: superior olivary complex
  relation: negatively_affects
  target: outer hair cell (OHC) - three rows
diagram_labels:
- amplification
- auditory perception processing
- central nervous system
- MET channel
- outer hair cell (OHC) - three rows
- outer hair cell (OHC) - three rows --+> SGN type II
- ribbon synapse
- ribbon synapse --+> SGN type I
- SGN type I
- SGN type II
- superior olivary complex
- various, non-sensory, supporting cell
diagram_other_links:
- href: /rgdweb/ontology/annot.html?acc_id=GO:0005546&species=All
  label: PIP2
references:
- id: RGD:8547546
  citation: 'Pan L and Zhang M, Physiology (Bethesda). 2012 Feb;27(1):25-42. doi: 10.1152/physiol.00037.2011.'
- id: RGD:8547667
  citation: 'Gillespie PG and Muller U, Cell. 2009 Oct 2;139(1):33-44. doi: 10.1016/j.cell.2009.09.010.'
- id: RGD:8547669
  citation: 'Schwander M, etal., J Cell Biol. 2010 Jul 12;190(1):9-20. doi: 10.1083/jcb.201001138.'
- id: RGD:8547671
  citation: 'Kazmierczak P and Muller U, Trends Neurosci. 2012 Apr;35(4):220-9. doi: 10.1016/j.tins.2011.10.007.
    Epub 2011 Dec 15.'
- id: RGD:8547672
  citation: 'Safieddine S, etal., Annu Rev Neurosci. 2012;35:509-28. doi: 10.1146/annurev-neuro-061010-113705.'
- id: RGD:8547673
  citation: 'Dror AA and Avraham KB, Neuron. 2010 Oct 21;68(2):293-308. doi: 10.1016/j.neuron.2010.10.011.'
- id: RGD:8547674
  citation: 'Lenz DR and Avraham KB, Hear Res. 2011 Nov;281(1-2):3-10. doi: 10.1016/j.heares.2011.05.021.
    Epub 2011 Jun 6.'
- id: RGD:8547676
  citation: 'Peng AW, etal., Nat Commun. 2011 Nov 1;2:523. doi: 10.1038/ncomms1533.'
- id: RGD:8547677
  citation: 'Drummond MC, etal., Hear Res. 2012 Jun;288(1-2):89-99. doi: 10.1016/j.heares.2011.12.003.
    Epub 2011 Dec 13.'
- id: RGD:8547678
  citation: 'Elgoyhen AB and Katz E, J Physiol Paris. 2012 Jan;106(1-2):47-56. doi: 10.1016/j.jphysparis.2011.06.001.
    Epub 2011 Jul 6.'
- id: RGD:8547679
  citation: 'Coate TM and Kelley MW, Semin Cell Dev Biol. 2013 May;24(5):460-9. doi: 10.1016/j.semcdb.2013.04.003.
    Epub 2013 May 6.'
- id: RGD:8547680
  citation: 'Mann ZF and Kelley MW, Hear Res. 2011 Jun;276(1-2):2-15. doi: 10.1016/j.heares.2011.01.011.
    Epub 2011 Jan 27.'