Search results for USH1C

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Protein (1 results from a total of 1)

Identifier: R-HSA-9658864
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: USH1C: Q9Y6N9

Interactor (1 results from a total of 1)

Identifier: Q9Y6N9-4
Species: Homo sapiens
Primary external reference: UniProt: Q9Y6N9-4

Complex (1 results from a total of 1)

Identifier: R-HSA-9658874
Species: Homo sapiens
Compartment: plasma membrane

Reaction (2 results from a total of 2)

Identifier: R-HSA-9663363
Species: Homo sapiens
Compartment: plasma membrane
The mechanoelectrical transduction (MET) channels located at the tips of stereocilia on the apical surface of outer hair cells (OHCs) are opened by mechanical force exerted on the channels by CDH23:PCDH15 tip links that connect the apices of shorter stereocilia to the sides of taller stereocilia (inferred from mouse homologs). A CDH23 dimer is connected to the cytoskeleton of a taller stereocilium via USH1C (Harmonin), USH1G (SANS), and MYO7A (MYOVIIA) (inferred from mouse homologs). By a calcium-dependent interaction, a CDH23 dimer on the side of a taller stereocilium is bound to a PCDH15 dimer connected to a MET channel on the apex of a shorter stereocilium (inferred from mouse homologs). The MET channel complex contains at least TMC1 or TMC2, TMIE, CIB2, and LHFPL5, with which PCDH15 interacts (inferred from mouse homologs). Deflection of the stereocilia by sound causes increased tension on CDH23:PCDH15, resulting in an increased probability of the open state of the MET channel. The MET channel is relatively non-specific for cations and conducts calcium ions and potassium ions from the extracellular scala media into the cytosol of the OHC. Depolarization of the OHC results in shortening of the OHC due to a change in conformation of SLC26A5 (prestin) located in the lateral membrane of the OHC. The composition of the cytoskeleton of OHCs differs from that of inner hair cells (IHCs): MPP1 and GSN are present in OHCs but absent from IHCs (inferred from mouse homologs).
Identifier: R-HSA-9659380
Species: Homo sapiens
Compartment: plasma membrane
The mechanoelectrical transduction (MET) channels located at the tips of stereocilia on the apical surface of inner hair cells are opened by mechanical force exerted on the channels by CDH23:PCDH15 tip links that connect the apex of the shorter stereocilium with the side of the taller stereocilium (inferred from mouse homologs and rat homologs). A CDH23 dimer is connected to the cytoskeleton of a taller stereocilium via USH1C (Harmonin), USH1G (SANS), and MYO7A (MYOVIIA) (inferred from mouse homologs). By a calcium-dependent interaction, a CDH23 dimer on the side of a taller stereocilium is bound to a PCDH15 dimer on the apex of a shorter stereocilium that interacts, possibly via LHFPL5, with a MET channel on the shorter stereocilium (inferred from mouse homologs). The MET complex contains at least TMC1 or TMC2, TMIE, CIB2, and LHFPL5, with which PCDH15 interacts (inferred from mouse homologs). The actual pore-forming units of the complex have not yet been identified with certainty. Deflection of the stereocilia by sound causes increased tension on CDH23:PCDH15, resulting in an increased probability of the open state of the MET channel (inferred from mouse homologs and rat homologs). The MET channel is relatively non-specific for cations and allows calcium ions and potassium ions to pass from the extracellular scala media to the cytosol of the inner hair cell (inferred from mouse homologs and rat homologs). The resulting depolarization of the cell eventually results in glutamate-mediated activation of myelinated afferent neurons of the cochlear nerve.

Pathway (1 results from a total of 1)

Identifier: R-HSA-9659379
Species: Homo sapiens
In mammals, sounds are processed in the cochlea, a spiral-shaped organ in the inner ear (reviewed in Basch et al. 2016, Fettiplace 2017, Koppl and Manley 2019). Low frequency sounds are sensed at the distal end (apex) of the cochlea; high frequency sounds are sensed at the proximal end (base) of the cochlea (reviewed in Dallos 1992, Manley 2018). Sound vibrations are transmitted from the eardrum through the three bones of the inner ear (malleus, incus, stapes) and the oval window of the cochlea to the fluids within the cochlea. Within the organ of Corti in the cochlea there are 3 rows of outer hair cells (OHCs) on the external side of the tunnel of Corti and 1 row of inner hair cells (IHCs) on the internal side (Spoendlin 1967). Each IHC synapses with approximately 20 afferent myelinated type I spiral ganglion neurons and functions as a sensory receptor to convert the energy of sound waves to secretion of glutamate neurotransmitter. Multiple OHCs synapse with each unmyelinated type II afferent neuron and OHCs are also synapsed with efferent medial olivocochlear fibers (Spoendlin 1967). The primary function of OHCs, however, is amplification of organ of Corti motions in response to sound (Ryan and Dallos 1975). Amplification is produced by changes in receptor-potential driven cell length caused by changes in the conformation of the unusual membrane protein prestin (SLC26A5, Zheng et al. 2000).
IHCs and OHCs sense the sonic vibrations by deflection of stereocilia on their apical surfaces (reviewed in Fettiplace et al. 2017, McPherson 2018). The stereocilia are arranged in rows of increasing height, with a stereocilium of one row connected to a stereocilium of another row by a tip link composed of a CDH23 dimer on the taller stereocilium joined at its N-termini to the N-termini of a PCDH15 dimer on the shorter stereocilium. CDH23 is connected to the cytoskeleton of the taller stereocilium via MYO7A (MyoVIIa), USH1C (Harmonin), and USH1G (Sans) (reviewed in Peng et al. 2011, Cosgrove and Zallocchi 2014, Barr-Gillespie 2015, Fettiplace 2017, McGrath et al. 2017, Cunningham and Müller 2019, Ó Maoiléidigh and Ricci 2019, Velez-Ortega and Frolenkov 2019) while PCDH15 on the shorter stereocilium interacts with LHFPL5, an auxiliary subunit of the mechanoelectrical transduction channel (MET channel, also known as the mechanotransduction channel), which contains at least TMC1 or TMC2, TMIE, and the auxiliary subunits LHFPL5 and CIB2 (reviewed in Fettiplace 2016, Qiu and Müller 2018, Corey et al. 2019). Deflection of stereocilia in the direction that increases tension on the tip link causes depolarization of the cell by increasing the open probability of the MET channel, which then transports calcium and potassium into the hair cell according to the gradient of those ions between the scala media (containing endolymph at 154 mM K+ and <1 mM Ca2+) at the apex of the cell and the scala tympani (containing perilymph at 7 mM K+) at the base (reviewed in Fettiplace and Kim 2014). Similarly, compression of the tip link by deflection of the stereocilia in the opposite direction decreases the open probability of the MET channel and causes hyperpolarization of the cell.
Depolarization of IHCs causes opening of voltage-gated calcium channels arrayed in stripes on the basolateral membrane close to ribbon synapses formed between the IHC and the afferent fiber of a myelinated type I spiral ganglion neuron. This results in a localized increase in cytosolic calcium ions which interact with Otoferlin (OTOF) on glutamate-containing synaptic vesicles at the ribbon structure to activate exocytosis of glutamate into the synapse formed with the afferent neuron (reviewed in Wichmann 2015, Pangrsic and Vogl 2018). Ribbon synapses are distinguished by electron-dense ribbon structures projecting from the presynaptic membrane into the cytosol and comprising at least BASSOON, RIBEYE (an isoform of CTBP2), and PICCOLINO (an isoform of PICCOLO). The ribbon structures appear to transiently bind synaptic vesicles and facilitate resupply of synaptic vesicles at active zones to refill the pool of readily releasable vesicles (reviewed in Moser et al. 2006, Moser et al. 2020).
In contrast with IHCs, OHCs mainly function in sound amplification by decreasing up to about 4% in length in response to depolarization caused by opening of the MET channel and increasing in length in response to hyperpolarization caused by channel closing, resulting in alternating compression and decompression between the reticular lamina and the basilar membrane. The changes in the length of the OHC are caused by very rapid (microseconds), voltage-sensitive changes in the conformation of the membrane protein prestin (SLC26A5). Stereociliary ATP2B2 (PMCA2) extrudes calcium ions and basally located KCNQ4 extrudes potassium ions to repolarize the OHC.
OHCs are synapsed with efferent cholinergic medial olivocochlear fibers (reviewed in Fritzsch and Elliott 2017, Fuchs and Lauer 2019). Acetylcholine released at the synapse binds an unusual, nicotine-antagonized, nicotinic receptor comprising CHRNA9 and CHRNA10. Upon binding acetylcholine, CHRNA9:CHRNA10 transports calcium ions into the OHC. The calcium activates SK2 potassium channels (KCNN2) and BK potassium channels (KCNMA1:KCNMB1) which extrude potassium ions, hyperpolarize the OHC, and inhibit activation of the OHC.
Loud sounds can cause a temporary threshold shift (temporary loss of hearing) caused by damage to stereocilia and synapses or permanent threshold shift (permanent loss of hearing) caused by damage or death of hair cells and neurons (reviewed in Kurabi et al. 2017).
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