Dataset Information

Ankyrin Is An Intracellular Tether for TMC Mechanotransduction Channels.

ABSTRACT: Mechanotransduction channels have been proposed as force sensors in various physiological processes, such as hearing and touch. In particular, TMC1 has been shown to constitute the pore of hair cell mechanotransduction channels, but little is known about how force is sensed by TMC channels. Here, we identify UNC-44/ankyrin as an essential component of the TMC-1 mechanotransduction channel complex in the sensory cilia of Caenorhabditis elegans mechanoreceptor neurons. Ankyrin binds indirectly to TMC-1 via evolutionarily conserved CIB proteins, which are required for TMC-1-mediated mechanosensation in C. elegans OLQ neurons and body wall muscles. Mechanosensory activity conferred by ectopically expressed TMCs in mechanoinsensitive neurons depends on both ankyrin and CIB proteins, indicating that the ankyrin-CIB subcomplex is required for TMC mechanosensitivity. Our work indicates that ankyrin is a long-sought intracellular tether that transmits force to TMC mechanotransduction channels.

SUBMITTER: Tang YQ

PROVIDER: S-EPMC7343241 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ankyrin Is An Intracellular Tether for TMC Mechanotransduction Channels.

Tang Yi-Quan YQ Lee Sol Ah SA Rahman Mizanur M Vanapalli Siva A SA Lu Hang H Schafer William R WR

Neuron 20200422 1

Mechanotransduction channels have been proposed as force sensors in various physiological processes, such as hearing and touch. In particular, TMC1 has been shown to constitute the pore of hair cell mechanotransduction channels, but little is known about how force is sensed by TMC channels. Here, we identify UNC-44/ankyrin as an essential component of the TMC-1 mechanotransduction channel complex in the sensory cilia of Caenorhabditis elegans mechanoreceptor neurons. Ankyrin binds indirectly to ...[more]

PMID: 32325031

Similar Datasets

Project description:Our senses of touch and hearing are dependent on the conversion of external mechanical forces into electrical impulses by the opening of mechanosensitive channels in sensory cells. This remarkable feat involves the conversion of a macroscopic mechanical displacement into a subnanoscopic conformational change within the ion channel. The mechanosensitive channel NOMPC, responsible for hearing and touch in flies, is a homotetramer composed of four pore-forming transmembrane domains and four helical chains of 29 ankyrin repeats that extend 150 Å into the cytoplasm. Previous work has shown that the ankyrin chains behave as biological springs under extension and that tethering them to microtubules could be involved in the transmission of external forces to the NOMPC gate. Here we combine normal mode analysis (NMA), full-atom molecular dynamics simulations, and continuum mechanics to characterize the material properties of the chains under extreme compression and extension. NMA reveals that the lowest-frequency modes of motion correspond to fourfold symmetric compression/extension along the channel, and the lowest-frequency symmetric mode for the isolated channel domain involves rotations of the TRP domain, a putative gating element. Finite element modeling reveals that the ankyrin chains behave as a soft spring with a linear, effective spring constantof 22 pN/nm for deflections ≤15 Å. Force-balance analysis shows that the entire channel undergoes rigid body rotation during compression, and more importantly, each chain exerts a positive twisting moment on its respective linker helices and TRP domain. This torque is a model-independent consequence of the bundle geometry and would cause a clockwise rotation of the TRP domain when viewed from the cytoplasm. Force transmission to the channel for compressions >15 Å depends on the nature of helix-helix contact. Our work reveals that compression of the ankyrin chains imparts a rotational torque on the TRP domain, which potentially results in channel opening.

Project description:Key pointsTrabecular meshwork (TM) is a highly mechanosensitive tissue in the eye that regulates intraocular pressure through the control of aqueous humour drainage. Its dysfunction underlies the progression of glaucoma but neither the mechanisms through which TM cells sense pressure nor their role in aqueous humour outflow are understood at the molecular level. We identified the Piezo1 channel as a key TM transducer of tensile stretch, shear flow and pressure. Its activation resulted in intracellular signals that altered organization of the cytoskeleton and cell-extracellular matrix contacts and modulated the trabecular component of aqueous outflow whereas another channel, TRPV4, mediated a delayed mechanoresponse. This study helps elucidate basic mechanotransduction properties that may contribute to intraocular pressure regulation in the vertebrate eye.AbstractChronic elevations in intraocular pressure (IOP) can cause blindness by compromising the function of trabecular meshwork (TM) cells in the anterior eye, but how these cells sense and transduce pressure stimuli is poorly understood. Here, we demonstrate functional expression of two mechanically activated channels in human TM cells. Pressure-induced cell stretch evoked a rapid increase in transmembrane current that was inhibited by antagonists of the mechanogated channel Piezo1, Ruthenium Red and GsMTx4, and attenuated in Piezo1-deficient cells. The majority of TM cells exhibited a delayed stretch-activated current that was mediated independently of Piezo1 by TRPV4 (transient receptor potential cation channel, subfamily V, member 4) channels. Piezo1 functions as the principal TM transducer of physiological levels of shear stress, with both shear and the Piezo1 agonist Yoda1 increasing the number of focal cell-matrix contacts. Analysis of TM-dependent fluid drainage from the anterior eye showed significant inhibition by GsMTx4. Collectively, these results suggest that TM mechanosensitivity utilizes kinetically, regulatory and functionally distinct pressure transducers to inform the cells about force-sensing contexts. Piezo1-dependent control of shear flow sensing, calcium homeostasis, cytoskeletal dynamics and pressure-dependent outflow suggests potential for a novel therapeutic target in treating glaucoma.

Dataset Information

Ankyrin Is An Intracellular Tether for TMC Mechanotransduction Channels.

Publications

Ankyrin Is An Intracellular Tether for TMC Mechanotransduction Channels.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets