id: MODULE:hair_cell_mechanotransduction title: Hair-cell mechanotransduction — CDH23/PCDH15 tip link, TMC1/TMC2 MET channel with LHFPL5/TMIE/CIB2, USH1 upper tip-link density tensioning, MYO1C adaptation and inner hair cell VGLUT3/otoferlin ribbon-synapse output; CDH23/PCDH15/TMC1/TMC2/LHFPL5/TMIE/CIB2/USH1C/USH1G/MYO7A/MYO1C/SLC17A8/OTOF description: >- Hair cells of the cochlea and of the vestibular organs convert deflection of their apical hair bundle into an electrical signal. The hair bundle is a staircase of actin-filled stereocilia. The tip of each shorter stereocilium is joined to the side of its taller neighbour by a tip link, a fine extracellular filament made of two cadherins: a parallel homodimer of cadherin 23 (CDH23) forms the upper part and a homodimer of protocadherin 15 (PCDH15) the lower part, and the two meet tip to tip. At the lower end of the tip link, PCDH15 is bound to the mechanoelectrical transduction (MET) channel complex in the stereocilium membrane. The pore of that channel is formed by the transmembrane channel-like protein TMC1, or by its paralog TMC2, which is expressed in vestibular hair cells and only transiently in neonatal cochlear hair cells. The tetraspan LHFPL5 (TMHS) and the two-pass TMIE couple PCDH15 to the pore, and the EF-hand protein CIB2 (with CIB3 in vestibular hair cells) binds the cytoplasmic side of TMC1/TMC2 and is needed for transduction. At the upper end of the tip link, CDH23 is anchored in the upper tip-link density, where the PDZ scaffold harmonin (USH1C), the scaffold SANS (USH1G) and the motor myosin VIIa (MYO7A) form a complex thought to hold the tip link under resting tension. Deflection of the bundle towards its tallest row raises tip-link tension and increases the open probability of the channels, and the resulting cation influx depolarises the cell. Sustained deflection is followed by adaptation; the slow component in vestibular hair cells is mediated by myosin-1c (MYO1C) slipping and climbing along the stereocilium actin core to reset tension. In inner hair cells of the cochlea, the receptor potential drives glutamate release at ribbon synapses onto type I spiral ganglion neurons. Synaptic vesicles are loaded with glutamate by the vesicular glutamate transporter VGLUT3 (SLC17A8), and Ca2+-triggered fusion requires otoferlin (OTOF), a multi-C2-domain protein that binds Ca2+ and the SNARE proteins and is the main Ca2+ sensor for exocytosis at this synapse. Outer hair cells use the same transduction apparatus to drive electromotile amplification. Loss-of-function variants in CDH23, PCDH15, USH1C, USH1G, MYO7A and CIB2 cause Usher syndrome type 1 or nonsyndromic deafness; variants in TMC1, LHFPL5 and TMIE cause nonsyndromic deafness; OTOF variants cause auditory neuropathy (DFNB9); and SLC17A8 variants cause DFNA25. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0001503 title: auditory mechanotransduction pathway statement: >- The module boundary follows the RGD Pathway Ontology record and diagram for this term. The record describes the hair bundle, the CDH23/PCDH15 tip link with its upper and lower tip-link densities, the MET channel at the lower end of the tip link, the harmonin, SANS, MYO7A and MYO1C proteins at the upper tip-link density, adaptation on fast and slow timescales, and the inner hair cell ribbon synapse that releases glutamate loaded by Slc17a8 (VGLUT3). The diagram draws Cdh23 associated with Pcdh15, Ush1c and Myo1c; Myo7a with Ush1c and Ush1g; Pcdh15 with Ush1c; Myo1c with PIP2; Espn with Myo3a; and Myo6 with Otof. Its 21 human genes are ACTB, ACTG1, ADGRV1, CDH23, ESPN, MYO15A, MYO1C, MYO3A, MYO6, MYO7A, OTOF, PCDH15, PLS1, PLS3, POTEI, PTPRQ, SLC17A8, USH1C, USH1G, USH2A and WHRN. Derived through projects/RGD_PATHWAY_ONTOLOGY (module seed PW:0001503; pathways/PW_0001503.yaml). - source_id: GO:0050910 title: detection of mechanical stimulus involved in sensory perception of sound statement: >- The curated narrowMatch for PW:0001503 in the project's PW-GO mappings; the mapping comment notes that the PW pathway also covers vestibular hair-cell transduction. The transduction parts of this module realise GO:0050910 in cochlear hair cells and its sibling GO:0050973 detection of mechanical stimulus involved in equilibrioception in vestibular hair cells. Both are is_a GO:0050974 detection of mechanical stimulus involved in sensory perception. The inner hair cell synaptic output is outside GO:0050910 but inside its parent GO:0007605 sensory perception of sound. - source_id: PMID:17805295 title: Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. statement: The tip link is a CDH23-PCDH15 filament thought to gate the transduction channel. supporting_text: Mechanoelectrical transduction takes place close to the tips of stereocilia in proximity to extracellular tip-link filaments that connect the stereocilia and are thought to gate the mechanoelectrical transduction channel. - source_id: PMID:23217710 title: TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells. statement: Tip links transmit tension onto the transduction channels. supporting_text: It is thought that tip links, fine extracellular filaments that connect the tips of neighboring stereocilia, transmit tension force onto the transduction channels notes: >- Derivation. Derived from the RGD Pathway Ontology record PW:0001503 through the RGD_PATHWAY_ONTOLOGY project's diagram->module route. No GO-CAM in gocams/index.tsv contains any of the RGD genes or the MET-channel subunits, and none uses GO:0050910 or GO:0050973, so the module has no gocam_associations. Of the 21 RGD human genes, 8 are modelled as participants (CDH23, PCDH15, USH1C, USH1G, MYO7A, MYO1C, SLC17A8, OTOF), 12 are excluded as bundle-building or bundle-maintaining proteins (decision 3), and POTEI is excluded as a mapping artefact (decision 6). Five MET-channel proteins that are not on the RGD list (TMC1, TMC2, LHFPL5, TMIE, CIB2) are added (decision 2). Boundary decisions. (1) Participant rule. CLAUDE.md requires that a product does some of the work of the process, not merely be needed for it. Nearly every hair-bundle protein is needed for transduction, because without a correctly built bundle no tip links form and no current flows; that is necessity evidence. The question asked for each RGD gene was which entity performs a step of detection: transmitting force (tip link), conducting the current (MET channel), setting or resetting tension on the channel (upper tip-link density and adaptation motor), or, in the output arm, loading and releasing transmitter. Comparator check (QuickGO, GO:0050910, human and mouse, October 2026): the term is carried by TMC1 and TMC2 (IMP involved_in, plus IBA), and by Pcdh15, Lhfpl5, Whrn, Ptprq, Adgrv1, Pdzd7, Strc, Atp2b2, Kcnq1, Slc12a2, Sox2, Myc, Chrna9/Chrna10 and others, mostly as acts_upstream_of_or_within from mouse phenotypes. The phenotype-based rows include transcription factors and the efferent nicotinic receptor, so the term in GOA does not mark direct participation, and its presence on a gene was not taken as a reason to add it. (2) MET channel. The RGD record calls the channel's identity unknown. Later work cached here identifies TMC1/TMC2 as the pore (PMID:30138589 "TMC1 forms the entire pore"; PMID:22105175; PMID:23871232), with LHFPL5 (PMID:23217710), TMIE (PMID:25467981) and CIB2/CIB3 (PMID:28663585, PMID:34089643) as required auxiliary subunits. Without them the module would have no transducer, so they are added. The channel is modelled as a protein complex with mechanosensitive monoatomic cation channel activity GO:0140135, following the TMC1 gene review, which records TMC1 as contributes_to GO:0140135 in cation channel complex GO:0034703 and proposes a new term "mechanoelectrical transduction channel complex" (not yet in GO). The pore subunit is a variant set: TMC1 in mature cochlear hair cells, TMC2 in vestibular hair cells and transiently in neonatal cochlear hair cells (PMID:22105175). LHFPL5 and TMIE carry no molecular function in GOA and are modelled only as active units of the complex. CIB2 is an active unit too; its gene-review core function ion channel regulator activity GO:0099106 is noted but not given a separate annoton, because the channel activity is a complex-level claim. CIB3 substitutes for or adds to CIB2 in vestibular hair cells (PMID:34089643); it is not grounded here because no CIB3 review or cached CIB3-specific paper beyond that one was read. TOMT, which is needed to traffic TMC proteins to the bundle, is a trafficking factor rather than a channel subunit and is not added. The candidate channel proteins TMEM63B, PIEZO1 (the reverse-polarity current) and TMC paralogs other than TMC1/TMC2 are not added. (3) Bundle architecture excluded. ACTB and ACTG1 (stereocilium actin core), ESPN, PLS1 and PLS3 (actin cross-linkers), MYO15A, WHRN and MYO3A (stereocilium length regulation and tip-complex delivery), PTPRQ (shaft connectors and phosphoinositide phosphatase at the stereocilium base), USH2A and ADGRV1 (transient ankle links) and MYO6 (cuticular plate and stereocilium rootlet anchoring) build or maintain the bundle in which transduction happens. Their process is inner ear receptor cell stereocilium organization GO:0060122 / auditory receptor cell stereocilium organization GO:0060088, as recorded in the WHRN, USH1C and ESPN reviews. They are context for this module, not steps, and a future stereocilium-organization module is the right home for them. Two disagreements are recorded rather than overridden. The ADGRV1 gene review lists GO:0050910 as a process of its ankle-link core function, citing reduced MET currents in Vlgr1-/- outer hair cells (PMID:17567809); that defect accompanies disorganised bundles and was read here as a developmental effect. Human PTPRQ carries GO:0050910 by IBA; mouse Ptprq mutants lose bundle integrity, which again is upstream of transduction. Both are worth a second look by the gene reviewers. USH1C harmonin-b also bundles F-actin (PMID:12485990); that role belongs with bundle architecture and is not modelled; only its upper-tip-link adaptor role is. (4) Upper tip-link density. Harmonin, SANS and MYO7A are kept as participants because the harmonin dfcr mutant loses the UTLD and has shifted channel sensitivity with a normal bundle (PMID:19447093), and MYO7A at the UTLD is proposed to generate the resting tip-link tension (PMID:21709241). Harmonin and SANS take the gene-review core function protein-macromolecule adaptor activity GO:0030674; MYO7A takes microfilament motor activity GO:0000146 (IDA, PMID:21687988; MYO7A review core). Whether MYO7A or MYO1C is the tensioning motor in cochlear hair cells is not settled (knowledge gap). (5) Adaptation. MYO1C is kept, as a separate part, because the Y61G chemical-genetic experiment blocked adaptation within seconds of inhibitor delivery in utricular hair cells (PMID:11853671), which is a test of participation, not of necessity. Its molecular function is microfilament motor activity GO:0000146 (mouse EXP, human IBA). The evidence comes from vestibular hair cells, and adaptation in cochlear hair cells is an order of magnitude faster and may use different molecules (PMID:19447093), so the part is marked optional and its cochlear role is a knowledge gap. Fast adaptation by Ca2+ entering through the channel itself is not given a separate participant. The RGD diagram edge Myo1c-PIP2 and the PTPRQ phosphoinositide gradient are noted but not modelled. (6) POTEI excluded. POTEI (UniProtKB:P0CG38) is a primate POTE ankyrin-domain protein whose C-terminal region belongs to the actin family. The rat diagram has no Pote gene, so POTEI most likely entered the human gene list through orthology mapping of rat Actb/Actg1 to an actin-like human sequence. Nothing links it to hair cells. (7) Synaptic output. The RGD record includes the inner hair cell ribbon synapse, so the two RGD genes that act there are modelled: SLC17A8 with L-glutamate uniporter activity GO:0140788 (IDA PMID:12151341 in GOA; a child of GO:0005313 used for the VGLUT family in modules/synaptic_vesicle_neurotransmitter_loading.yaml, whose glutamate_loading variant grounds only VGLUT1/VGLUT2), and OTOF with calcium ion sensor activity GO:0061891, the term the synaptic_vesicle_exocytosis module uses for synaptotagmins (OTOF GOA has calcium ion binding GO:0005509 IDA PMID:17055430; the UniProt function text calls it the key Ca2+ sensor of IHC ribbon-synapse fusion). The generic SNARE, priming and active-zone machinery is in modules/synaptic_vesicle_exocytosis.yaml and is not repeated; the IHC synapse is atypical (otoferlin rather than synaptotagmin-1/2 as sensor), so a module_ref to that module was not used as a part. The CaV1.3 channel (CACNA1D) that couples the receptor potential to release, the ribbon protein RIBEYE (CTBP2) and the postsynaptic AMPA receptors of spiral ganglion neurons are not on the RGD list and are not modelled; the connection from the MET channel to exocytosis is therefore indirect. The MYO6-OTOF interaction drawn by RGD is noted but not modelled. (8) Out of scope: outer hair cell electromotility (prestin, SLC26A5; GO:0099129), the medial olivocochlear efferent synapse (CHRNA9/CHRNA10), the tectorial membrane and otolithic membrane, hair-cell development and planar polarity, and the endolymph potassium recycling that supplies the transduction current. Cochlear versus vestibular. The transduction parts are shared by cochlear and vestibular hair cells; the differences captured are the TMC1/TMC2 pore variants and the vestibular provenance of the MYO1C evidence. The ribbon-synapse output is modelled for cochlear inner hair cells only; vestibular hair cells also have ribbon synapses, but VGLUT3 is the IHC transporter named by RGD. Gene reviews used: CDH23, TMC1, CIB2, MYO7A, USH1C and USH1G core functions. PCDH15, TMC2, LHFPL5, TMIE, MYO1C, OTOF and SLC17A8 have no review yet; their functions come from GOA and the cited literature. PANTHER family ids and PTNs are deliberately not asserted. module: id: hair_cell_mechanotransduction label: Hair-cell mechanotransduction module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: detection of mechanical stimulus involved in sensory perception of sound term: id: GO:0050910 label: detection of mechanical stimulus involved in sensory perception of sound description: >- Conversion of hair-bundle deflection into a receptor current in cochlear hair cells; the curated narrowMatch of PW:0001503. - preferred_term: detection of mechanical stimulus involved in equilibrioception term: id: GO:0050973 label: detection of mechanical stimulus involved in equilibrioception description: >- The same apparatus in vestibular hair cells, which the PW pathway also covers. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: >- Members are grounded on the human proteins; most functional evidence comes from mouse hair cells. cell_types: - preferred_term: cochlear inner hair cell term: id: CL:0000589 label: cochlear inner hair cell - preferred_term: cochlear outer hair cell term: id: CL:0000601 label: cochlear outer hair cell - preferred_term: vestibular hair cell term: id: CL:0000609 label: vestibular hair cell cellular_components: - preferred_term: stereocilium term: id: GO:0032420 label: stereocilium description: >- The transduction parts act in the stereocilia of the hair bundle; tip-link, tip-density and synaptic locations are given on the annotons. parts: - order: 1 role: force transmission by the tip link node: id: tip_link label: CDH23-PCDH15 tip link module_type: BIOLOGICAL_PROCESS description: >- CDH23 homodimers from the taller stereocilium bind PCDH15 homodimers from the shorter stereocilium tip to tip, forming the tip-link filament. Bundle deflection changes tip-link tension, which is passed to the MET channel at the PCDH15 end. annotons: - id: cdh23_upper_tip_link label: CDH23 forms the upper part of the tip link participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CDH23 (cadherin 23) term: id: UniProtKB:Q9H251 label: Cadherin-23 function: preferred_term: cadherin binding term: id: GO:0045296 label: cadherin binding targets: - preferred_term: PCDH15 (protocadherin 15) term: id: UniProtKB:Q96QU1 label: Protocadherin-15 processes: - preferred_term: detection of mechanical stimulus involved in sensory perception of sound term: id: GO:0050910 label: detection of mechanical stimulus involved in sensory perception of sound locations: - preferred_term: stereocilia tip link term: id: GO:0002140 label: stereocilia tip link role_description: >- Upper tip-link strand, anchored in the upper tip-link density of the taller stereocilium; its cytoplasmic tail binds harmonin. The function follows the CDH23 gene-review core function. evidence: - source_id: PMID:17805295 statement: CDH23 and PCDH15 form the upper and lower parts of the tip link. supporting_text: cadherin 23 (CDH23) and protocadherin 15 (PCDH15) localize to the upper and lower part of tip links, respectively. - source_id: PMID:17805295 statement: CDH23 homodimers bind PCDH15 homodimers in trans to form a tip-link-like filament. supporting_text: Biochemical experiments show that CDH23 homodimers interact in trans with PCDH15 homodimers to form a filament with structural similarity to tip links. - id: pcdh15_lower_tip_link label: PCDH15 forms the lower part of the tip link participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PCDH15 (protocadherin 15) term: id: UniProtKB:Q96QU1 label: Protocadherin-15 function: preferred_term: cell adhesion molecule binding term: id: GO:0050839 label: cell adhesion molecule binding targets: - preferred_term: CDH23 (cadherin 23) term: id: UniProtKB:Q9H251 label: Cadherin-23 processes: - preferred_term: detection of mechanical stimulus involved in sensory perception of sound term: id: GO:0050910 label: detection of mechanical stimulus involved in sensory perception of sound locations: - preferred_term: stereocilia tip link term: id: GO:0002140 label: stereocilia tip link role_description: >- Lower tip-link strand, inserted at the tip of the shorter stereocilium, where it binds LHFPL5 and TMIE and so couples the tip link to the channel. The function is the human IBA row; PCDH15 has no gene review yet. evidence: - source_id: PMID:17805295 statement: A deafness mutation in PCDH15 disrupts the CDH23-PCDH15 interaction. supporting_text: Ions that affect tip-link integrity and a mutation in PCDH15 that causes a recessive form of deafness disrupt interactions between CDH23 and PCDH15. - source_id: PMID:23217710 statement: LHFPL5 (TMHS) couples PCDH15 to the transduction channel. supporting_text: TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel. - order: 2 role: mechanoelectrical transduction channel node: id: met_channel label: TMC1/TMC2 MET channel complex module_type: PROTEIN_COMPLEX description: >- The non-selective, Ca2+-permeable cation channel at the lower end of the tip link. A dimeric TMC pore subunit assembles with LHFPL5, TMIE and CIB2; tip-link tension raises its open probability and the inward current depolarises the hair cell. variant_sets: - id: met_pore_subunit label: TMC1 and TMC2 pore subunits axis: hair-cell type and developmental stage selection: ONE_OR_MORE notes: >- TMC1 is the pore of mature cochlear hair cells; TMC2 is expressed in vestibular hair cells and transiently in neonatal cochlear hair cells. Loss of both abolishes transduction. variants: - id: tmc1_met_channel label: TMC1-containing MET channel module_type: PROTEIN_COMPLEX annotons: - id: tmc1_met_channel_activity label: TMC1 MET channel mechanosensitive cation channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: TMC1 mechanoelectrical transduction channel complex term: id: GO:0034703 label: cation channel complex active_units: - id: tmc1_pore_unit label: TMC1 pore-forming subunit role: Dimeric pore-forming subunit; its S4-S7 helices line the permeation pathway. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TMC1 term: id: UniProtKB:Q8TDI8 label: Transmembrane channel-like protein 1 - id: lhfpl5_unit_tmc1 label: LHFPL5 (TMHS) auxiliary subunit role: Tetraspan subunit that binds PCDH15 and couples the tip link to the pore. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LHFPL5 (TMHS) term: id: UniProtKB:Q8TAF8 label: LHFPL tetraspan subfamily member 5 protein - id: tmie_unit_tmc1 label: TMIE auxiliary subunit role: Two-pass subunit linking the PCDH15/LHFPL5 complex to the TMC pore. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TMIE term: id: UniProtKB:Q8NEW7 label: Transmembrane inner ear expressed protein - id: cib2_unit_tmc1 label: CIB2 auxiliary subunit role: Cytoplasmic EF-hand subunit bound to TMC1/TMC2, required for transduction. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CIB2 term: id: UniProtKB:O75838 label: Calcium and integrin-binding family member 2 function: preferred_term: mechanosensitive monoatomic cation channel activity term: id: GO:0140135 label: mechanosensitive monoatomic cation channel activity processes: - preferred_term: detection of mechanical stimulus involved in sensory perception of sound term: id: GO:0050910 label: detection of mechanical stimulus involved in sensory perception of sound locations: - preferred_term: stereocilium tip term: id: GO:0032426 label: stereocilium tip role_description: >- The transducer of mature cochlear hair cells. The function follows the TMC1 gene review (contributes_to GO:0140135 in a cation channel complex). evidence: - source_id: PMID:30138589 statement: TMC1 forms the pore of the hair-cell transduction channel. supporting_text: TMC1 forms the entire pore. - source_id: PMID:25467981 statement: TMIE links the PCDH15/LHFPL5 complex to the pore-forming subunits. supporting_text: We also show that TMIE establishes a critical link between the PCDH15/LHFPL5 complex and the pore-forming subunits of the transduction channel. - source_id: PMID:28663585 statement: CIB2 binds TMC1 and TMC2 and is needed for transduction in auditory hair cells. supporting_text: Here, we show that CIB2 interacts with the MET channel components TMC1 and TMC2, is essential for MET function and regulating the length of transducing shorter row stereocilia in mammalian auditory hair cells. - source_id: PMID:34089643 statement: CIB2 and CIB3 are auxiliary subunits of the channel. supporting_text: CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells. - id: tmc2_met_channel label: TMC2-containing MET channel module_type: PROTEIN_COMPLEX annotons: - id: tmc2_met_channel_activity label: TMC2 MET channel mechanosensitive cation channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: TMC2 mechanoelectrical transduction channel complex term: id: GO:0034703 label: cation channel complex active_units: - id: tmc2_pore_unit label: TMC2 pore-forming subunit role: Pore-forming paralog of TMC1 in vestibular and neonatal cochlear hair cells. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TMC2 term: id: UniProtKB:Q8TDI7 label: Transmembrane channel-like protein 2 - id: lhfpl5_unit_tmc2 label: LHFPL5 (TMHS) auxiliary subunit role: Tetraspan subunit that binds PCDH15 and couples the tip link to the pore. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LHFPL5 (TMHS) term: id: UniProtKB:Q8TAF8 label: LHFPL tetraspan subfamily member 5 protein - id: tmie_unit_tmc2 label: TMIE auxiliary subunit role: Two-pass subunit linking the PCDH15/LHFPL5 complex to the TMC pore. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TMIE term: id: UniProtKB:Q8NEW7 label: Transmembrane inner ear expressed protein - id: cib2_unit_tmc2 label: CIB2 auxiliary subunit (with CIB3 in vestibular hair cells) role: Cytoplasmic EF-hand subunit bound to TMC1/TMC2; vestibular hair cells also express CIB3. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CIB2 term: id: UniProtKB:O75838 label: Calcium and integrin-binding family member 2 function: preferred_term: mechanosensitive monoatomic cation channel activity term: id: GO:0140135 label: mechanosensitive monoatomic cation channel activity processes: - preferred_term: detection of mechanical stimulus involved in equilibrioception term: id: GO:0050973 label: detection of mechanical stimulus involved in equilibrioception - preferred_term: detection of mechanical stimulus involved in sensory perception of sound term: id: GO:0050910 label: detection of mechanical stimulus involved in sensory perception of sound locations: - preferred_term: stereocilium tip term: id: GO:0032426 label: stereocilium tip role_description: >- The vestibular and neonatal cochlear transducer; TMC2 sets permeation properties distinct from TMC1. evidence: - source_id: PMID:22105175 statement: TMC2 is transient in cochlear hair cells but persists in vestibular hair cells. supporting_text: Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. - source_id: PMID:22105175 statement: Loss of both TMC1 and TMC2 abolishes transduction in structurally normal hair cells. supporting_text: Tmc1 Δ Tmc2 Δ mice had profound vestibular dysfunction, deafness, and structurally normal hair cells that lacked all mechanotransduction activity. - source_id: PMID:23871232 statement: TMC1 and TMC2 are channel components that set permeation properties. supporting_text: The data demonstrate TMC1 and TMC2 are components of hair cell transduction channels and contribute to permeation properties. - source_id: PMID:34089643 statement: Vestibular hair cells express both CIB2 and CIB3. supporting_text: For unknown reasons, vestibular hair cells express both CIB2 and CIB3. - order: 3 role: tip-link anchoring and resting tension node: id: upper_tip_link_density label: USH1 complex at the upper tip-link density module_type: PROTEIN_COMPLEX description: >- At the upper end of the tip link, harmonin binds the CDH23 cytoplasmic tail and, with SANS, links it to myosin VIIa and the actin core. The complex is thought to hold the tip link under resting tension and sets the sensitivity of the channels to displacement. annotons: - id: ush1c_utld_adaptor label: Harmonin (USH1C) UTLD adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: USH1C (harmonin, b isoforms) term: id: UniProtKB:Q9Y6N9 label: Harmonin function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity targets: - preferred_term: CDH23 (cadherin 23) term: id: UniProtKB:Q9H251 label: Cadherin-23 processes: - preferred_term: detection of mechanical stimulus involved in sensory perception of sound term: id: GO:0050910 label: detection of mechanical stimulus involved in sensory perception of sound locations: - preferred_term: upper tip-link density term: id: GO:1990435 label: upper tip-link density role_description: >- Anchors CDH23 at the UTLD; the USH1C gene-review core function. evidence: - source_id: PMID:19447093 statement: Harmonin is a UTLD component that sets channel sensitivity to displacement. supporting_text: We conclude that harmonin is a UTLD component and contributes to establishing the sensitivity of mechanotransduction channels to displacement. - id: ush1g_utld_adaptor label: SANS (USH1G) UTLD adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: USH1G (SANS) term: id: UniProtKB:Q495M9 label: pre-mRNA splicing regulator USH1G function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity targets: - preferred_term: USH1C (harmonin) term: id: UniProtKB:Q9Y6N9 label: Harmonin - preferred_term: MYO7A (myosin VIIa) term: id: UniProtKB:Q13402 label: Unconventional myosin-VIIa processes: - preferred_term: detection of mechanical stimulus involved in sensory perception of sound term: id: GO:0050910 label: detection of mechanical stimulus involved in sensory perception of sound locations: - preferred_term: upper tip-link density term: id: GO:1990435 label: upper tip-link density role_description: >- Scaffold that locks onto harmonin and binds the MYO7A tail; the first USH1G gene-review core function. evidence: - source_id: PMID:20142502 statement: Harmonin and SANS form a highly stable scaffold complex. supporting_text: We further show that the synergistic PDZ1/SAM and PDZ1/carboxyl PDZ binding-motif interactions, between harmonin and Sans, lock the two scaffold proteins into a highly stable complex. - source_id: PMID:21709241 statement: MYO7A and SANS cluster at the UTLD. supporting_text: Using immunofluorescence, we now show that MYO7A and sans, a MYO7A-interacting protein, cluster at the UTLD. - id: myo7a_utld_motor label: Myosin VIIa tensioning motor at the UTLD participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MYO7A (myosin VIIa) term: id: UniProtKB:Q13402 label: Unconventional myosin-VIIa function: preferred_term: microfilament motor activity term: id: GO:0000146 label: microfilament motor activity processes: - preferred_term: detection of mechanical stimulus involved in sensory perception of sound term: id: GO:0050910 label: detection of mechanical stimulus involved in sensory perception of sound locations: - preferred_term: upper tip-link density term: id: GO:1990435 label: upper tip-link density role_description: >- Slow, high-duty-ratio motor proposed to pull on CDH23 and hold the tip link under tension; the MYO7A gene-review hair-cell core function. evidence: - source_id: PMID:21709241 statement: MYO7A is likely the motor that tensions the tip link. supporting_text: In this complex, MYO7A is likely the motor element that pulls on CDH23 to exert tension on the tip-link. - source_id: PMID:21687988 statement: Human myosin-7a is a slow, high-duty-ratio motor suited to holding tension. supporting_text: These specific kinetic adaptations indicate that human myosin-7a is a slow molecular motor with a high duty ratio, suitable for moving cargoes and mediating tension in the cytoskeleton. - order: 4 role: slow adaptation optional: true notes: >- Optional because the evidence is from vestibular hair cells; cochlear adaptation is faster and may use other molecules. node: id: myo1c_adaptation label: MYO1C adaptation motor module_type: REGULATORY_STEP description: >- During a sustained deflection the adaptation motor slips down the actin core, lowering tip-link tension and channel open probability; on return it climbs to restore tension. annotons: - id: myo1c_adaptation_motor label: Myosin-1c adaptation motor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MYO1C (myosin-1c) term: id: UniProtKB:O00159 label: Unconventional myosin-Ic function: preferred_term: microfilament motor activity term: id: GO:0000146 label: microfilament motor activity processes: - preferred_term: detection of mechanical stimulus involved in equilibrioception term: id: GO:0050973 label: detection of mechanical stimulus involved in equilibrioception locations: - preferred_term: stereocilium tip term: id: GO:0032426 label: stereocilium tip role_description: >- Slow-adaptation motor of vestibular hair cells, shown by acute chemical-genetic inhibition; MYO1C has no gene review yet. evidence: - source_id: PMID:11853671 statement: Acute inhibition of sensitised myosin-1c blocks adaptation in utricular hair cells. supporting_text: found that the analog rapidly blocked adaptation to positive and negative deflections in transgenic cells but not in wild-type cells. - source_id: PMID:19447093 statement: MYO1C adaptation models rest on vestibular hair cells. supporting_text: It should also be noted that current models of MYO1C function in adaptation are largely based on the study of vestibular hair cells. - order: 5 role: vesicular glutamate loading in inner hair cells node: id: ihc_glutamate_loading label: VGLUT3 loads inner hair cell synaptic vesicles module_type: TRANSPORT_STEP description: >- VGLUT3 (SLC17A8), the only vesicular glutamate transporter of inner hair cells, fills ribbon-associated synaptic vesicles with glutamate. annotons: - id: slc17a8_glutamate_uniporter label: SLC17A8 (VGLUT3) L-glutamate uniporter participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SLC17A8 (VGLUT3) term: id: UniProtKB:Q8NDX2 label: Vesicular glutamate transporter 3 function: preferred_term: L-glutamate uniporter activity term: id: GO:0140788 label: L-glutamate uniporter activity processes: - preferred_term: neurotransmitter loading into synaptic vesicle term: id: GO:0098700 label: neurotransmitter loading into synaptic vesicle locations: - preferred_term: synaptic vesicle membrane term: id: GO:0030672 label: synaptic vesicle membrane role_description: >- The IHC glutamate transporter named by RGD; VGLUT3-null mice are deaf because IHCs release no glutamate. See also synaptic_vesicle_neurotransmitter_loading#glutamate_loading. evidence: - source_id: PMID:18674745 statement: VGLUT3 loads glutamate into IHC synaptic vesicles. supporting_text: In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals. - source_id: PMID:18215623 statement: Without VGLUT3 hair cells release no glutamate and mice are deaf. supporting_text: We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway. - order: 6 role: Ca2+-triggered exocytosis at the inner hair cell ribbon synapse node: id: ihc_ribbon_exocytosis label: Otoferlin-dependent ribbon-synapse exocytosis module_type: BIOLOGICAL_PROCESS description: >- Depolarisation opens presynaptic Ca2+ channels at the active zone; Ca2+-bound otoferlin engages the SNAREs and triggers fusion of ribbon-tethered vesicles, releasing glutamate onto type I spiral ganglion neurons. annotons: - id: otof_calcium_sensor label: Otoferlin Ca2+ sensor for vesicle fusion participant: selector_type: GENE_PRODUCT gene_product: preferred_term: OTOF (otoferlin) term: id: UniProtKB:Q9HC10 label: Otoferlin function: preferred_term: calcium ion sensor activity term: id: GO:0061891 label: calcium ion sensor activity processes: - preferred_term: synaptic vesicle exocytosis term: id: GO:0016079 label: synaptic vesicle exocytosis locations: - preferred_term: cochlear hair cell ribbon synapse term: id: GO:0098683 label: cochlear hair cell ribbon synapse role_description: >- The main Ca2+ sensor for exocytosis at the IHC ribbon synapse; OTOF has no gene review yet. The generic fusion machinery is in synaptic_vesicle_exocytosis. evidence: - source_id: PMID:17055430 statement: Otoferlin binds Ca2+ and interacts with SNAREs in a Ca2+-dependent manner. supporting_text: Otoferlin binds Ca(2+) and displays Ca(2+)-dependent interactions with the SNARE proteins syntaxin1 and SNAP25. - source_id: PMID:17055430 statement: IHC exocytosis is nearly abolished without otoferlin, which may be the main Ca2+ sensor. supporting_text: Thus, otoferlin is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the IHC ribbon synapse. connections: - source: tip_link target: met_channel connection_type: POSITIVELY_REGULATES description: >- Increased tip-link tension during deflection towards the tallest row is passed through PCDH15, LHFPL5 and TMIE to the pore and raises channel open probability. - source: upper_tip_link_density target: tip_link connection_type: POSITIVELY_REGULATES description: >- The harmonin-SANS-MYO7A complex anchors CDH23 and holds the tip link under resting tension. - source: myo1c_adaptation target: tip_link connection_type: NEGATIVELY_REGULATES description: >- During sustained deflection the adaptation motor slips, lowering tip-link tension and so channel open probability. - source: met_channel target: ihc_ribbon_exocytosis connection_type: POSITIVELY_REGULATES description: >- The transduction current depolarises the inner hair cell, which opens the presynaptic Ca2+ channels (CaV1.3, not modelled) that trigger otoferlin-dependent release. - source: ihc_glutamate_loading target: ihc_ribbon_exocytosis connection_type: PROVIDES_INPUT_FOR description: VGLUT3-loaded vesicles are the glutamate quanta released at the ribbon synapse. knowledge_gaps: - gap_statement: >- Which motor sets resting tip-link tension and mediates slow adaptation in cochlear hair cells is unresolved; MYO7A localises to the upper tip-link density, while the MYO1C adaptation evidence comes from vestibular hair cells. boundary: >- MYO7A is modelled as the UTLD tensioning motor and MYO1C as an optional adaptation part restricted to equilibrioception; neither is asserted as the cochlear adaptation motor. gap_kind: - BIOLOGY status: OPEN significance: Determines whether the tensioning and adaptation steps are one motor or two in the cochlea. resolution: >- Acute, motor-specific inhibition (for example analog-sensitive MYO7A or MYO1C alleles) in mature cochlear hair cells with measurement of resting open probability and adaptation kinetics. provenance: - reference_id: PMID:21709241 supporting_text: However, localization studies are conflicting, leaving open the question of which myosin localizes at the UTLD and generates the tip-link resting tension. - reference_id: PMID:19447093 supporting_text: It should also be noted that current models of MYO1C function in adaptation are largely based on the study of vestibular hair cells. - gap_statement: >- How tip-link tension is conveyed from PCDH15 through LHFPL5 and TMIE to open the TMC pore, and the stoichiometry of the native complex, are not established in mammalian hair cells. boundary: >- The channel is modelled as one complex with mechanosensitive cation channel activity; no gating mechanism or stoichiometry is asserted. gap_kind: - BIOLOGY status: OPEN significance: The gating mechanism is the core unknown of hair-cell transduction. resolution: >- Structures of the native mammalian complex under tension and site-directed perturbation of the PCDH15-LHFPL5-TMIE-TMC1 interfaces with transduction recordings. provenance: - reference_id: PMID:25467981 supporting_text: We also show that TMIE establishes a critical link between the PCDH15/LHFPL5 complex and the pore-forming subunits of the transduction channel.