Home LiteratureArticle Details
PMID: 23217710 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells.

Cell ·Vol. 151 ·No. 6 ·2012-12-07 ·Pages 1283-95

Xiong W, Grillet N, Elledge HM, Wagner TF, Zhao B, Johnson KR, Kazmierczak P, Müller U

Abstract

Hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.

MeSH Terms
Animals Cadherin Related Proteins Cadherins/metabolism Hair Cells, Auditory/metabolism Hearing Mechanotransduction, Cellular Membrane Proteins/genetics,metabolism,ultrastructure Mice Mice, Knockout Protein Precursors/metabolism Stereocilia/metabolism
Chemicals
CDHR15 protein, mouse Cadherin Related Proteins Cadherins LHFPL5 protein, mouse Membrane Proteins Protein Precursors
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Xiong Wei
The Dorris Neuroscience Center, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Grillet Nicolas
Elledge Heather M
Wagner Thomas F J
Zhao Bo
Johnson Kenneth R
Kazmierczak Piotr
Müller Ulrich
References (52)
52 references, click to expand
  1. Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids.
    Hum Mol Genet. 2010 Sep 15;19(18):3557-65 PMID: 20639393
  2. Harmonin-b, an actin-binding scaffold protein, is involved in the adaptation of mechanoelectrical transduction by sensory hair cells.
    Pflugers Arch. 2009 Nov;459(1):115-30 PMID: 19756723
  3. A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function.
    J Neurosci. 2007 Feb 28;27(9):2163-75 PMID: 17329413
  4. Piezo proteins are pore-forming subunits of mechanically activated channels.
    Nature. 2012 Feb 19;483(7388):176-81 PMID: 22343900
  5. Interactions in the network of Usher syndrome type 1 proteins.
    Hum Mol Genet. 2005 Feb 1;14(3):347-56 PMID: 15590703
  6. Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice.
    Genomics. 2001 Jun 1;74(2):228-33 PMID: 11386759
  7. A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells.
    Cell. 2002 Feb 8;108(3):371-81 PMID: 11853671
  8. Tonotopic variation in the conductance of the hair cell mechanotransducer channel.
    Neuron. 2003 Dec 4;40(5):983-90 PMID: 14659096
  9. Harmonin mutations cause mechanotransduction defects in cochlear hair cells.
    Neuron. 2009 May 14;62(3):375-87 PMID: 19447093
  10. Mutations of human TMHS cause recessively inherited non-syndromic hearing loss.
    J Med Genet. 2006 Aug;43(8):634-40 PMID: 16459341
  11. Tip links in hair cells: molecular composition and role in hearing loss.
    Curr Opin Otolaryngol Head Neck Surg. 2009 Oct;17(5):388-93 PMID: 19633555
  12. A large-conductance calcium-selective mechanotransducer channel in mammalian cochlear hair cells.
    J Neurosci. 2006 Oct 25;26(43):10992-1000 PMID: 17065441
  13. Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans.
    Am J Hum Genet. 2009 Sep;85(3):328-37 PMID: 19732867
  14. A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry-scurry (hscy) mice.
    Proc Natl Acad Sci U S A. 2005 May 31;102(22):7894-9 PMID: 15905332
  15. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells.
    Nature. 2007 Sep 6;449(7158):87-91 PMID: 17805295
  16. The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit.
    Nat Genet. 1998 Aug;19(4):340-7 PMID: 9697694
  17. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes.
    J Clin Invest. 2011 Dec;121(12):4796-809 PMID: 22105175
  18. Cadherin 23 is a component of the transient lateral links in the developing hair bundles of cochlear sensory cells.
    Dev Biol. 2005 Apr 15;280(2):281-94 PMID: 15882573
  19. Localization and targeting of voltage-dependent ion channels in mammalian central neurons.
    Physiol Rev. 2008 Oct;88(4):1407-47 PMID: 18923186
  20. Fast adaptation of mechanoelectrical transducer channels in mammalian cochlear hair cells.
    Nat Neurosci. 2003 Aug;6(8):832-6 PMID: 12872124
  21. Supramolecular assemblies and localized regulation of voltage-gated ion channels.
    Physiol Rev. 2009 Apr;89(2):411-52 PMID: 19342611
  22. The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions.
    Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14946-51 PMID: 12407180
  23. The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15.
    J Neurosci. 2006 Jun 28;26(26):7022-34 PMID: 16807332
  24. Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells.
    Nature. 2004 Apr 29;428(6986):955-9 PMID: 15057246
  25. The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene.
    Nat Genet. 2001 Jan;27(1):99-102 PMID: 11138007
  26. Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators.
    Nat Methods. 2009 Dec;6(12):875-81 PMID: 19898485
  27. The transduction channel filter in auditory hair cells.
    J Neurosci. 2005 Aug 24;25(34):7831-9 PMID: 16120785
  28. Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations.
    Nat Neurosci. 2002 Jan;5(1):41-7 PMID: 11753415
  29. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.
    Nature. 2006 May 11;441(7090):179-85 PMID: 16582901
  30. Mechanotransduction by hair cells: models, molecules, and mechanisms.
    Cell. 2009 Oct 2;139(1):33-44 PMID: 19804752
  31. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry.
    Science. 2006 May 26;312(5777):1220-3 PMID: 16645049
  32. Fast adaptation in vestibular hair cells requires myosin-1c activity.
    Neuron. 2005 Aug 18;47(4):541-53 PMID: 16102537
  33. Genetics of hearing loss: Allelism and modifier genes produce a phenotypic continuum.
    Anat Rec A Discov Mol Cell Evol Biol. 2006 Apr;288(4):370-81 PMID: 16550584
  34. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels.
    Science. 2010 Oct 1;330(6000):55-60 PMID: 20813920
  35. Physical and functional interaction between protocadherin 15 and myosin VIIa in mechanosensory hair cells.
    J Neurosci. 2006 Feb 15;26(7):2060-71 PMID: 16481439
  36. Cadherin 23 is a component of the tip link in hair-cell stereocilia.
    Nature. 2004 Apr 29;428(6986):950-5 PMID: 15057245
  37. Targeted knockout and lacZ reporter expression of the mouse Tmhs deafness gene and characterization of the hscy-2J mutation.
    Mamm Genome. 2007 Sep;18(9):646-56 PMID: 17876667
  38. Spatiotemporal pattern and isoforms of cadherin 23 in wild type and waltzer mice during inner ear hair cell development.
    Dev Biol. 2005 Apr 15;280(2):295-306 PMID: 15882574
  39. A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth.
    Development. 2008 Apr;135(8):1427-37 PMID: 18339676
  40. Ancillary subunits associated with voltage-dependent K+ channels.
    Physiol Rev. 2010 Apr;90(2):755-96 PMID: 20393197
  41. Tetraspanin-enriched microdomains: a functional unit in cell plasma membranes.
    Trends Cell Biol. 2009 Sep;19(9):434-46 PMID: 19709882
  42. Development and properties of stereociliary link types in hair cells of the mouse cochlea.
    J Comp Neurol. 2005 Apr 25;485(1):75-85 PMID: 15776440
  43. Stepwise morphological and functional maturation of mechanotransduction in rat outer hair cells.
    J Neurosci. 2007 Dec 12;27(50):13890-902 PMID: 18077701
  44. Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle.
    EMBO J. 2002 Dec 16;21(24):6689-99 PMID: 12485990
  45. The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits.
    Neuron. 2011 Apr 28;70(2):178-99 PMID: 21521608
  46. Primary structure of the gamma subunit of the DHP-sensitive calcium channel from skeletal muscle.
    Science. 1990 Apr 27;248(4954):490-2 PMID: 2158672
  47. Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain.
    Development. 2011 Apr;138(8):1607-17 PMID: 21427143
  48. Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D.
    Nat Genet. 2001 Jan;27(1):103-7 PMID: 11138008
  49. Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia.
    Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5825-30 PMID: 21436032
  50. A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells.
    Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5252-7 PMID: 19270079
  51. Localization of inner hair cell mechanotransducer channels using high-speed calcium imaging.
    Nat Neurosci. 2009 May;12(5):553-8 PMID: 19330002
  52. Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction.
    Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11476-81 PMID: 21709241
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.10.041
Published
2012-12-07
Pages
1283-95
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3522178
Subset
IM
Grants
NIDCD NIH HHS · DC007704 · United States
NIDCD NIH HHS · R01 DC007704 · United States
NIDCD NIH HHS · DC005965 · United States
NIDCD NIH HHS · R01 DC005965 · United States
NIDCD NIH HHS · R01 DC004301 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2012.10.041 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2