Molecular Crux of Hair Cell Mechanotransduction Machinery

Al-Sheikh, Umar; Kang, Lijun

doi:10.1016/j.neuron.2020.07.007

Cited by 12 publications

(9 citation statements)

References 12 publications

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“…Mechanosensitive channels can be made up of several subunits. For example, in hair cell, mechanoelectrical transduction channels consist of transmembrane channel-like 1 and 2 (TMC1/2), transmembrane inner ear (TMIE), transmembrane proteins lipoma HMGIC fusion partner-like 5 (TMHS/LHFPL5), and may be more [24].…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM structure of the human TACAN channel in a closed state

Chen

Wang

et al. 2021

Preprint

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TACAN is an ion channel involved in sensing mechanical pain. It has recently been shown to represent a novel and evolutionarily conserved class of mechanosensitive channels. Here, we present the cryoelectron microscopic structure of human TACAN (hTACAN). hTACAN forms a dimer in which each protomer consists of a transmembrane globular domain (TMD) that is formed of six helices and an intracellular domain (ICD) that is formed of two helices. Molecular dynamic simulations suggest that a putative ion conduction pathway is located inside each protomer. Single point mutation of the key residue Met207 significantly increased the surface tension activated currents. Moreover, cholesterols were identified at the flank of each subunit. Our data show the molecular assembly of hTACAN and suggest that the wild type hTACAN is in a closed state, providing a basis for further understanding the activation mechanism of the hTACAN channel.

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Section: Discussionmentioning

confidence: 99%

Cryo-EM structure of the human TACAN channel in a closed state

Chen

Wang

et al. 2021

Preprint

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“…MeT channels open very quickly and the channel latencies are typically less than 20 ms [31,41,52]. To date, members of four classes of membrane proteins that are related to mechanotransduction are considered to be pore-forming subunits of MeT channels: TRP, DEG/ENaC, Piezo, and TMC [31,32,34,38,53,54]. mechanotransduction channels [21,38,40,52].…”

Section: A Novel Sodium-sensitive Channel In Mechanotransductionmentioning

confidence: 99%

Polymodal Functionality of C. elegans OLL Neurons in Mechanosensation and Thermosensation

et al. 2021

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Sensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca2+ transients and rapidly-adapting mechanoreceptor currents with a very short latency. Mechanotransduction of OLL neurons might be carried by a novel Na+ conductance channel, which is insensitive to amiloride. The bona fide mechano-gated Na+-selective degenerin/epithelial Na+ channels, TRP-4, TMC, and Piezo proteins are not involved in this mechanosensation. Interestingly, OLL neurons also mediated cold but not warm responses in a cell-autonomous manner. We further showed that the cold response of OLL neurons is not mediated by the cold receptor TRPA-1 or the temperature-sensitive glutamate receptor GLR-3. Thus, we propose the polymodal functionality of OLL neurons in mechanosensation and cold sensation.

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“…The single-tether model is simple with an intracellular tether and membrane forces congregate to regulate the passage of ions across the channel (Chalfie, 2009). The gating mechanism of hair cell mechanotransduction might be very complex incorporating features of known tethering models and more (Al-Sheikh & Kang, 2020). For instance, ankyrin recently reported to tether the cytoskeleton and the TMC/CIB complex, conforms to the dual-tether model alongside the tip link proteins (PCDH15/CDH23) (Tang et al, 2020).…”

Section: Gating Mechanismmentioning

confidence: 99%

“…Whereas, another latest study about TMIE and PIP 2 (Phosphatidylinositol 4, 5-bisphosphate) revealed to promote membrane tension and mechanosensation (Cunningham et al, 2020). As such, the mammalian hair cell mechanotransduction machinery is still enigmatic even after 62 years since the first report of hereditary deafness in a mouse model (Al-Sheikh & Kang, 2020).…”

Section: Gating Mechanismmentioning

confidence: 99%

“…Previous studies have demonstrated that Piezo2 required for cutaneous Merkel cell mechanotransduction, plays a major role in light-touch mechanosensation (Woo et al, 2014). Strikingly, latest reports reveal that TMC1/2, TMIE, PCDH15/CDH23, CIB, ankyrin and PIP 2 serve as key gating components of hair cell mechanotransduction channel, in charge of mammalian hearing and balance (Al-Sheikh & Kang, 2020). However, most channel proteins engaged in mechanosensation may not be the primary mechanoreceptor but function indirectly as a secondary messenger in response to a mechanical stimulus (Christensen & Corey, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Mechano-gated channels in C. elegans

Al-Sheikh

Kang

2020

Journal of Neurogenetics

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Mechanosensation such as touch, hearing and proprioception, is functionally regulated by mechanogated ion channels through the process of transduction. Mechano-gated channels are a subtype of gated ion channels engaged in converting mechanical stimuli to chemical or electrical signals thereby modulating sensation. To date, a few families of mechano-gated channels (DEG/ENaC, TRPN, K 2 P, TMC and Piezo) have been identified in eukaryotes. Using a tractable genetic model organism Caenorhabditis elegans, the molecular mechanism of mechanosensation have been the focus of much research to comprehend the process of mechanotransduction. Comprising of almost all metazoans classes of ion channels, transporters and receptors, C. elegans is a powerful genetic model to explore mechanosensitive behaviors such as touch sensation and proprioception. The nematode relies primarily on its sensory abilities to survive in its natural environment. Genetic screening, calcium imaging and electrophysiological analysis have established that ENaC proteins and TRPN channel (TRP-4 protein) can characterize mechano-gated channels in C. elegans. A recent study reported that TMCs are likely the pore-forming subunit of a mechano-gated channel in C. elegans. Nevertheless, it still remains unclear whether Piezo as well as other candidate proteins can form mechano-gated channels in C. elegans.

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Molecular Crux of Hair Cell Mechanotransduction Machinery

Abstract: Although 62 years have elapsed since the first report of hereditary deafness in a mouse strain, the molecular mechanism of hair cell mechanotransduction remains elusive. Three recent studies present crucial insights into the molecular crux of hair cell mechanotransduction machinery.

Cited by 12 publications

References 12 publications

Cryo-EM structure of the human TACAN channel in a closed state

Cryo-EM structure of the human TACAN channel in a closed state

Polymodal Functionality of C. elegans OLL Neurons in Mechanosensation and Thermosensation

Mechano-gated channels in C. elegans

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