Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing

被引:22
作者
Ballesteros, Angela [1 ]
Swartz, Kenton J. [1 ]
机构
[1] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA
关键词
OUTER HAIR-CELLS; MECHANOTRANSDUCTION-CHANNEL; MECHANICAL TRANSDUCTION; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; PHOSPHATIDYLSERINE EXPOSURE; SENSORY TRANSDUCTION; COCHLEAR CULTURES; PLASMA-MEMBRANE; INNER; PORE;
D O I
10.1126/sciadv.abm5550
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The mechanoelectrical transduction (MET) channel in auditory hair cells converts sound into electrical signals, enabling hearing. Transmembrane-like channel 1 and 2 (TMC1 and TMC2) are implicated in forming the pore of the MET channel. Here, we demonstrate that inhibition of MET channels, breakage of the tip links required for MET, or buffering of intracellular Ca-... induces pronounced phosphatidylserine externalization, membrane blebbing, and ectosome release at the hair cell sensory organelle, culminating in the loss of TMC1. Membrane homeostasis triggered by MET channel inhibition requires Tmc1 but not Tmc2, and three deafness-causing mutations in Tmc1 cause constitutive phosphatidylserine externalization that correlates with deafness phenotype. Our results suggest that, in addition to forming the pore of the MET channel, TMC1 is a critical regulator of membrane homeostasis in hair cells, and that Tmc1-related hearing loss may involve alterations in membrane homeostasis.
引用
收藏
页数:18
相关论文
共 91 条
[1]   Functional Hair Cell Mechanotransducer Channels Are Required for Aminoglycoside Ototoxicity [J].
Alharazneh, Abdelrahman ;
Luk, Lauren ;
Huth, Markus ;
Monfared, Ashkan ;
Steyger, Peter S. ;
Cheng, Alan G. ;
Ricci, Anthony J. .
PLOS ONE, 2011, 6 (07)
[2]   Transgenic Tmc2 expression preserves inner ear hair cells and vestibular function in mice lacking Tmc1 [J].
Asai, Yukako ;
Pan, Bifeng ;
Nist-Lund, Carl ;
Galvin, Alice ;
Lukashkin, Andrei N. ;
Lukashkina, Victoria A. ;
Chen, Tianwen ;
Zhou, Wu ;
Zhu, Hong ;
Russell, Ian J. ;
Holt, Jeffrey R. ;
Geleoc, Gwenaelle S. G. .
SCIENTIFIC REPORTS, 2018, 8
[3]   TIP-LINK INTEGRITY AND MECHANICAL TRANSDUCTION IN VERTEBRATE HAIR-CELLS [J].
ASSAD, JA ;
SHEPHERD, GMG ;
COREY, DP .
NEURON, 1991, 7 (06) :985-994
[4]   Expression of a membrane-targeted fluorescent reporter disrupts auditory hair cell mechanoelectrical transduction and causes profound deafness [J].
Ballesteros, Angela ;
Fitzgerald, Tracy S. ;
Swartz, Kenton J. .
HEARING RESEARCH, 2021, 404
[5]   Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins [J].
Ballesteros, Angela ;
Fenollar-Ferrer, Cristina ;
Swartz, Kenton Jon .
ELIFE, 2018, 7
[6]   New Tmc1 Deafness Mutations Impact Mechanotransduction in Auditory Hair Cells [J].
Beurg, Maryline ;
Schimmenti, Lisa A. ;
Koleilat, Alaa ;
Amr, Sami S. ;
Oza, Andrea ;
Barlow, Amanda J. ;
Ballesteros, Angela ;
Fettiplace, Robert .
JOURNAL OF NEUROSCIENCE, 2021, 41 (20) :4378-4391
[7]   A Tmc1 mutation reduces calcium permeability and expression of mechanoelectrical transduction channels in cochlear hair cells [J].
Beurg, Maryline ;
Barlow, Amanda ;
Furness, David N. ;
Fettiplace, Robert .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (41) :20743-20749
[8]   Variable number of TMC1-dependent mechanotransducer channels underlie tonotopic conductance gradients in the cochlea [J].
Beurg, Maryline ;
Cui, Runjia ;
Goldring, Adam C. ;
Ebrahim, Seham ;
Fettiplace, Robert ;
Kachar, Bechara .
NATURE COMMUNICATIONS, 2018, 9
[9]   The effects of Tmc1 Beethoven mutation on mechanotransducer channel function in cochlear hair cells [J].
Beurg, Maryline ;
Goldring, Adam C. ;
Fettiplace, Robert .
JOURNAL OF GENERAL PHYSIOLOGY, 2015, 146 (03) :233-243
[10]   Calcium Balance and Mechanotransduction in Rat Cochlear Hair Cells [J].
Beurg, Maryline ;
Nam, Jong-Hoon ;
Chen, Qingguo ;
Fettiplace, Robert .
JOURNAL OF NEUROPHYSIOLOGY, 2010, 104 (01) :18-34