The Murine Catecholamine Methyltransferase MTOMT is Essential for Mechanotransduction by Cochlear Hair Cells

Overview

Journal Elife

Specialty Biology

Date 2017 May 16

PMID 28504928

Citations 22

Authors

Christopher L Cunningham

Zizhen Wu

Aria Jafari

Bo Zhao

Kat Schrode

Sarah Harkins-Perry

Amanda Lauer

Ulrich Muller

Affiliations

Soon will be listed here.

Abstract

Hair cells of the cochlea are mechanosensors for the perception of sound. Mutations in the gene, which encodes a protein with homology to the catecholamine methyltransferase COMT that is linked to schizophrenia, cause deafness. Here, we show that , the murine ortholog of , has an unexpected function in the regulation of mechanotransduction by hair cells. The role of mTOMT in hair cells is independent of mTOMT methyltransferase function and mCOMT cannot substitute for mTOMT function. Instead, mTOMT binds to putative components of the mechanotransduction channel in hair cells and is essential for the transport of some of these components into the mechanically sensitive stereocilia of hair cells. Our studies thus suggest functional diversification between mCOMT and mTOMT, where mTOMT is critical for the assembly of the mechanotransduction machinery of hair cells. Defects in this process are likely mechanistically linked to deafness caused by mutations in .

Citing Articles

Inhibition of GABARAP or GABARAPL1 prevents aminoglycoside- induced hearing loss.

Li J, Oh S, Liu C, Zhao B Proc Natl Acad Sci U S A. 2025; 122(7):e2416453122.

PMID: 39928869 PMC: 11848329. DOI: 10.1073/pnas.2416453122.

Single molecule studies of the native hair cell mechanosensory transduction complex.

Clark S, Mitra J, Elferich J, Goehring A, Ge J, Ha T bioRxiv. 2024; .

PMID: 38168376 PMC: 10760052. DOI: 10.1101/2023.12.11.571162.

Transmembrane Channel-Like (Tmc) Subunits Contribute to Frequency Sensitivity in the Zebrafish Utricle.

Sun P, Smith E, Nicolson T J Neurosci. 2023; 44(1).

PMID: 37952940 PMC: 10851681. DOI: 10.1523/JNEUROSCI.1298-23.2023.

The monoaminergic system is a bilaterian innovation.

Goulty M, Botton-Amiot G, Rosato E, Sprecher S, Feuda R Nat Commun. 2023; 14(1):3284.

PMID: 37280201 PMC: 10244343. DOI: 10.1038/s41467-023-39030-2.

Mechanoelectrical transduction-related genetic forms of hearing loss.

Jung J, Muller U Curr Opin Physiol. 2023; 32.

PMID: 36936795 PMC: 10022594. DOI: 10.1016/j.cophys.2023.100632.

References

Pan B, Geleoc G, Asai Y, Horwitz G, Kurima K, Ishikawa K . TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron. 2013; 79(3):504-15. PMC: 3827726. DOI: 10.1016/j.neuron.2013.06.019. View

Du X, Schwander M, Moresco E, Viviani P, Haller C, Hildebrand M . A catechol-O-methyltransferase that is essential for auditory function in mice and humans. Proc Natl Acad Sci U S A. 2008; 105(38):14609-14. PMC: 2567147. DOI: 10.1073/pnas.0807219105. View

Zhang J, Klinman J . Enzymatic methyl transfer: role of an active site residue in generating active site compaction that correlates with catalytic efficiency. J Am Chem Soc. 2011; 133(43):17134-7. PMC: 3219439. DOI: 10.1021/ja207467d. View

Mannisto P, Kaakkola S . Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev. 1999; 51(4):593-628. View

Marcotti W, Corns L, Desmonds T, Kirkwood N, Richardson G, Kros C . Transduction without tip links in cochlear hair cells is mediated by ion channels with permeation properties distinct from those of the mechano-electrical transducer channel. J Neurosci. 2014; 34(16):5505-14. PMC: 3988408. DOI: 10.1523/JNEUROSCI.4086-13.2014. View

Ahmed Z, Goodyear R, Riazuddin S, Lagziel A, Legan P, Behra M . The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15. J Neurosci. 2006; 26(26):7022-34. PMC: 6673907. DOI: 10.1523/JNEUROSCI.1163-06.2006. View

Belyantseva I, Boger E, Naz S, Frolenkov G, Sellers J, Ahmed Z . Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nat Cell Biol. 2005; 7(2):148-56. DOI: 10.1038/ncb1219. View

Alharazneh A, Luk L, Huth M, Monfared A, Steyger P, Cheng A . Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PLoS One. 2011; 6(7):e22347. PMC: 3144223. DOI: 10.1371/journal.pone.0022347. View

Tunbridge E . The catechol-O-methyltransferase gene: its regulation and polymorphisms. Int Rev Neurobiol. 2010; 95:7-27. DOI: 10.1016/B978-0-12-381326-8.00002-8. View

10.

Kawashima Y, Geleoc G, Kurima K, Labay V, Lelli A, Asai Y . Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clin Invest. 2011; 121(12):4796-809. PMC: 3223072. DOI: 10.1172/JCI60405. View

11.

Sei Y, Li Z, Song J, Ren-Patterson R, Tunbridge E, Iizuka Y . Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. PLoS One. 2010; 5(5):e10789. PMC: 2875391. DOI: 10.1371/journal.pone.0010789. View

12.

Kemp D . Stimulated acoustic emissions from within the human auditory system. J Acoust Soc Am. 1978; 64(5):1386-91. DOI: 10.1121/1.382104. View

13.

Kazmierczak P, Muller U . Sensing sound: molecules that orchestrate mechanotransduction by hair cells. Trends Neurosci. 2011; 35(4):220-9. PMC: 3310959. DOI: 10.1016/j.tins.2011.10.007. View

14.

Darrow K, Simons E, Dodds L, Liberman M . Dopaminergic innervation of the mouse inner ear: evidence for a separate cytochemical group of cochlear efferent fibers. J Comp Neurol. 2006; 498(3):403-14. PMC: 1805779. DOI: 10.1002/cne.21050. View

15.

Beurg M, Xiong W, Zhao B, Muller U, Fettiplace R . Subunit determination of the conductance of hair-cell mechanotransducer channels. Proc Natl Acad Sci U S A. 2015; 112(5):1589-94. PMC: 4321290. DOI: 10.1073/pnas.1420906112. View

16.

Labay V, Weichert R, Makishima T, Griffith A . Topology of transmembrane channel-like gene 1 protein. Biochemistry. 2010; 49(39):8592-8. PMC: 3005947. DOI: 10.1021/bi1004377. View

17.

Gogos J, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D . Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci U S A. 1998; 95(17):9991-6. PMC: 21449. DOI: 10.1073/pnas.95.17.9991. View

18.

Zhao B, Muller U . The elusive mechanotransduction machinery of hair cells. Curr Opin Neurobiol. 2015; 34:172-9. PMC: 4632855. DOI: 10.1016/j.conb.2015.08.006. View

19.

Ahmed Z, Masmoudi S, Kalay E, Belyantseva I, Mosrati M, Collin R . Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans. Nat Genet. 2008; 40(11):1335-40. PMC: 3404732. DOI: 10.1038/ng.245. View

20.

Kim K, Beurg M, Hackney C, Furness D, Mahendrasingam S, Fettiplace R . The role of transmembrane channel-like proteins in the operation of hair cell mechanotransducer channels. J Gen Physiol. 2013; 142(5):493-505. PMC: 3813385. DOI: 10.1085/jgp.201311068. View