scholarly journals Permeation properties of the hair cell mechanotransducer channel provide insight into its molecular structure

2012 ◽  
Vol 107 (9) ◽  
pp. 2408-2420 ◽  
Author(s):  
B. Pan ◽  
J. Waguespack ◽  
M. E. Schnee ◽  
C. LeBlanc ◽  
A. J. Ricci
Keyword(s):  
Hair Cells ◽  
Apparent Difference ◽  
Channel Conductance ◽  
Critical Function ◽  
Molecular Identity ◽  
Sensory Hair Cells ◽  
Molecular Components ◽  
Channel Properties ◽  
Permeation Properties ◽  
Insight Into

Mechanoelectric transducer (MET) channels, located near stereocilia tips, are opened by deflecting the hair bundle of sensory hair cells. Defects in this process result in deafness. Despite this critical function, the molecular identity of MET channels remains a mystery. Inherent channel properties, particularly those associated with permeation, provide the backbone for the molecular identification of ion channels. Here, a novel channel rectification mechanism is identified, resulting in a reduced pore size at positive potentials. The apparent difference in pore dimensions results from Ca2+ binding within the pore, occluding permeation. Driving force for permeation at hyperpolarized potentials is increased because Ca2+ can more easily be removed from binding within the pore due to the presence of an electronegative external vestibule that dehydrates and concentrates permeating ions. Alterations in Ca2+ binding may underlie tonotopic and Ca2+-dependent variations in channel conductance. This Ca2+-dependent rectification provides targets for identifying the molecular components of the MET channel.

scholarly journals In Silico Electrophysiology of Inner-Ear Mechanotransduction Channel TMC1 Models

2021 ◽  
Author(s):  
Sanket Walujkar ◽  
Jeffrey M Lotthammer ◽  
Collin R Nisler ◽  
Joseph C Sudar ◽  
Angela Ballesteros ◽  
...  
Keyword(s):  
Inner Ear ◽  
Conformational Changes ◽  
Hair Cells ◽  
Head Movements ◽  
Mechanical Stimuli ◽  
Ion Conduction ◽  
Sensory Hair Cells ◽  
Activation Mechanisms ◽  
Dynamics Simulations ◽  
Molecular Components

Inner-ear sensory hair cells convert mechanical stimuli from sound and head movements into electrical signals during mechanotransduction. Identification of all molecular components of the inner-ear mechanotransduction apparatus is ongoing; however, there is strong evidence that TMC1 and TMC2 are pore-forming subunits of the complex. We present molecular dynamics simulations that probe ion conduction of TMC1 models built based on two different structures of related TMEM16 proteins. Unlike most channels, the TMC1 models do not show a central pore. Instead, simulations of these models in a membrane environment at various voltages reveal a peripheral permeation pathway that is exposed to lipids and that shows cation permeation at rates comparable to those measured in hair cells. Furthermore, our analyses suggest that TMC1 gating mechanisms involve protein conformational changes and tension-induced lipid-mediated pore widening. These results provide insights into ion conduction and activation mechanisms of hair-cell mechanotransduction channels essential for hearing and balance.

From Funny Current to HCN Channels: 20 Years of Excitation

Physiology ◽  
2002 ◽  
Vol 17 (1) ◽  
pp. 32-37 ◽  
Author(s):  
E. A. Accili ◽  
C. Proenza ◽  
M. Baruscotti ◽  
D. DiFrancesco
Keyword(s):  
Molecular Basis ◽  
Single Channel ◽  
Cardiac Cells ◽  
Hcn Channels ◽  
Pacemaker Current ◽  
Channel Conductance ◽  
Single Channel Conductance ◽  
Pacemaker Channels ◽  
Channel Properties ◽  
Insight Into

The “funny” (pacemaker) current has unusual characteristics, including activation on hyperpolarization, permeability to K+ and Na+, modulation by internal cAMP, and a tiny, single-channel conductance. In cardiac cells and neurons, pacemaker channels control repetitive activity and excitability. The recent cloning of HCN subunits provides new insight into the molecular basis for the funny channel properties.

scholarly journals Molecular Identity and Functional Properties of a Novel T-Type Ca2+ Channel Cloned From the Sensory Epithelia of the Mouse Inner Ear

2008 ◽  
Vol 100 (4) ◽  
pp. 2287-2299 ◽  
Author(s):  
Liping Nie ◽  
Jun Zhu ◽  
Michael Anne Gratton ◽  
Amy Liao ◽  
Karen J. Mu ◽  
...  
Keyword(s):  
Inner Ear ◽  
Hair Cells ◽  
Synapse Formation ◽  
Divalent Cations ◽  
Functional Expression ◽  
Basilar Papilla ◽  
Vestibular Hair Cells ◽  
Molecular Identity ◽  
Sensory Epithelia ◽  
Permeation Properties

The molecular identity of non-Cav1.3 channels in auditory and vestibular hair cells has remained obscure, yet the evidence in support of their roles to promote diverse Ca2+-dependent functions is indisputable. Recently, a transient Cav3.1 current that serves as a functional signature for the development and regeneration of hair cells has been identified in the chicken basilar papilla. The Cav3.1 current promotes spontaneous activity of the developing hair cell, which may be essential for synapse formation. Here, we have isolated and sequenced the full-length complementary DNA of a distinct isoform of Cav3.1 in the mouse inner ear. The channel is derived from alternative splicing of exon14, exon25A, exon34, and exon35. Functional expression of the channel in Xenopus oocytes yielded Ca2+ currents, which have a permeation phenotype consistent with T-type channels. However, unlike most multiion channels, the T-type channel does not exhibit the anomalous mole fraction effect, possibly reflecting comparable permeation properties of divalent cations. The Cav3.1 channel was expressed in sensory and nonsensory epithelia of the inner ear. Moreover, there are profound changes in the expression levels during development. The differential expression of the channel during development and the pharmacology of the inner ear Cav3.1 channel may have contributed to the difficulties associated with identification of the non-Cav1.3 currents.

scholarly journals TPXL-1 Activates Aurora A to Clear Contractile Ring Components from the Polar Cortex During Cytokinesis

2017 ◽  
Author(s):  
Sriyash Mangal ◽  
Jennifer Sacher ◽  
Taekyung Kim ◽  
Daniel Sampaio Osório ◽  
Fumio Motegi ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Contractile Ring ◽  
Inhibitory Signal ◽  
Molecular Identity ◽  
Anaphase Onset ◽  
Cortical Contractility ◽  
Molecular Components ◽  
Insight Into

ABSTRACTDuring cytokinesis, a signal from the bundled microtubules that form between the separating anaphase chromosomes promotes the accumulation of contractile ring components at the cell equator, while a signal from the centrosomal microtubule asters inhibits accumulation of contractile ring components at the cell poles. However, the molecular identity of the inhibitory signal has remained unknown. To identify molecular components of the aster-based inhibitory signal, we developed a means to monitor the removal of contractile ring proteins from the polar cortex after anaphase onset. Using this assay, we show that polar clearing is an active process that requires activation of Aurora A kinase by TPXL-1. TPXL-1 concentrates on astral microtubules coincident with polar clearing in anaphase, and its ability to recruit Aurora A and activate its kinase activity are essential for clearing. In summary, our data identify Aurora A kinase as an aster-based inhibitory signal that restricts contractile ring components to the cell equator during cytokinesis.SUMMARYDuring cytokinesis, centrosomal asters inhibit cortical contractility at the cell poles. Mangal et al. provide molecular insight into this phenomenon, showing that TPXL-1, which localizes to astral microtubules, activates Aurora A kinase to clear contractile ring proteins from the polar cortex.

scholarly journals Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Angela Ballesteros ◽  
Cristina Fenollar-Ferrer ◽  
Kenton Jon Swartz
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Genetic Alterations ◽  
Structural Relationship ◽  
Large Cavity ◽  
X Ray ◽  
Molecular Identity ◽  
Transmembrane Channel ◽  
Tip Link ◽  
Channel Properties

The hair cell mechanotransduction (MET) channel complex is essential for hearing, yet it’s molecular identity and structure remain elusive. The transmembrane channel–like 1 (TMC1) protein localizes to the site of the MET channel, interacts with the tip-link responsible for mechanical gating, and genetic alterations in TMC1 alter MET channel properties and cause deafness, supporting the hypothesis that TMC1 forms the MET channel. We generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that also harbors the Beethoven mutation, suggesting that it could function as a permeation pathway. We also find that hair cells are permeable to 3 kDa dextrans, and that dextran permeation requires TMC1/2 proteins and functional MET channels, supporting the presence of a large permeation pathway and the hypothesis that TMC1 is a pore forming subunit of the MET channel complex.

scholarly journals Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins

2018 ◽  
Author(s):  
Angela Ballesteros ◽  
Cristina Fenollar-Ferrer ◽  
Kenton J. Swartz
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Genetic Alterations ◽  
Structural Relationship ◽  
Large Cavity ◽  
X Ray ◽  
Molecular Identity ◽  
Transmembrane Channel ◽  
Tip Link ◽  
Channel Properties

AbstractThe hair cell mechanotransduction (MET) channel complex is essential for hearing, yet it’s molecular identity and structure remain elusive. The transmembrane channel-like 1 (TMC1) protein localizes to the site of the MET channel, interacts with the tip-link responsible for mechanical gating, and genetic alterations in TMC1 alter MET channel properties and cause deafness, supporting the hypothesis that TMC1 forms the MET channel. We generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that also harbors the Beethoven mutation, suggesting that it could function as a permeation pathway. We also find that hair cells are permeable to 3 kDa dextrans, and that dextran permeation requires TMC1/2 proteins and functional MET channels, supporting the presence of a large permeation pathway and the hypothesis that TMC1 is a pore forming subunit of the MET channel complex.

Ultrastructure of superficial neuromasts in the mottled sculpin, Cottus bairdi

1989 ◽  
Vol 47 ◽  
pp. 958-959
Author(s):  
W.R. Jones ◽  
S. Coombs ◽  
J. Janssen
Keyword(s):  
Hair Cells ◽  
Lateral Line System ◽  
Electron Microscopic ◽  
Line System ◽  
Dense Cores ◽  
Sensory Hair Cells ◽  
Cytoplasmic Vesicles ◽  
Cottus Bairdi ◽  
Mottled Sculpin ◽  
Upper Third

The lateral line system of the mottled sculpin, like that of most bony fish, has both canal (CNM) and superficial (SNM) sensory end organs, neuromasts, which are distributed on the head and trunk in discrete, readily identifiable groupings (Fig. 1). CNM and SNM differ grossly in location and in overall size and shape. The former are located in subdermal canals and are larger and asymmetric in shape, The latter are located directly on the surface of the skin and are much smaller and more symmetrical It has been suggested that the two may differ at a more fundamental level in such functionally related parameters as extent of myelination of innervating fibers and the absence of efferent innervation in SNM. The present study addresses the validity of these last two features as distinguishing criteria by examining the structure of those SNM populations indicated in Fig. 1 at both the light and electron microscopic levels.All of the populations of SNM examined conform in general to previously published descriptions, consisting of a neuroepithelium composed of sensory hair cells, support cells and mantle cells, Several significant differences from these accounts have, however, emerged. Firstly, the structural composition of the innervating fibers is heterogeneous with respect to the extent of myelination. All SNM groups, with the possible exception of the TRrs and CFLs, possess both myelinated and unmyelinated fibers within the neuroepithelium proper (Fig. 2), just as do CNM. The extent of myelina- tion is quite variable, with some fibers sheath terminating just before crossing the neuroepithelial basal lamina, some just after and a few retaining their myelination all the way to the base of the hair cells in the upper third of the neuroepithelium. Secondly, all SNMs possess fibers that may, on the basis of ultrastructural criteria, be identified as efferent. Such fibers contained numerous cytoplasmic vesicles, both clear and with dense cores. In regions where such fibers closely apposed hair cells, subsynaptic cisternae were observed in the hair cell (Fig. 3).

scholarly journals Synaptically silent sensory hair cells in zebrafish are recruited after damage

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Qiuxiang Zhang ◽  
Suna Li ◽  
Hiu-Tung C. Wong ◽  
Xinyi J. He ◽  
Alisha Beirl ◽  
...  
Keyword(s):  
Hair Cells ◽  
Sensory Hair ◽  
Sensory Hair Cells

Molecular anatomy and physiology of exocytosis in sensory hair cells

Cell Calcium ◽  
2012 ◽  
Vol 52 (3-4) ◽  
pp. 327-337 ◽  
Author(s):  
Mark A. Rutherford ◽  
Tina Pangršič
Keyword(s):  
Hair Cells ◽  
Sensory Hair ◽  
Anatomy And Physiology ◽  
Sensory Hair Cells ◽  
Molecular Anatomy

scholarly journals Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia

2004 ◽  
Vol 166 (4) ◽  
pp. 559-570 ◽  
Author(s):  
Shin-ichiro Kitajiri ◽  
Kanehisa Fukumoto ◽  
Masaki Hata ◽  
Hiroyuki Sasaki ◽  
Tatsuya Katsuno ◽  
...  
Keyword(s):  
Hair Cells ◽  
Plasma Membranes ◽  
Wild Type ◽  
Cross Link ◽  
Erm Proteins ◽  
Hearing Ability ◽  
Adult Mice ◽  
Progressive Degeneration ◽  
Sensory Hair Cells

Ezrin/radixin/moesin (ERM) proteins cross-link actin filaments to plasma membranes to integrate the function of cortical layers, especially microvilli. We found that in cochlear and vestibular sensory hair cells of adult wild-type mice, radixin was specifically enriched in stereocilia, specially developed giant microvilli, and that radixin-deficient (Rdx−/−) adult mice exhibited deafness but no obvious vestibular dysfunction. Before the age of hearing onset (∼2 wk), in the cochlea and vestibule of Rdx−/− mice, stereocilia developed normally in which ezrin was concentrated. As these Rdx−/− mice grew, ezrin-based cochlear stereocilia progressively degenerated, causing deafness, whereas ezrin-based vestibular stereocilia were maintained normally in adult Rdx−/− mice. Thus, we concluded that radixin is indispensable for the hearing ability in mice through the maintenance of cochlear stereocilia, once developed. In Rdx−/− mice, ezrin appeared to compensate for radixin deficiency in terms of the development of cochlear stereocilia and the development/maintenance of vestibular stereocilia. These findings indicated the existence of complicate functional redundancy in situ among ERM proteins.

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