TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells

Pan, Bifeng; Akyuz, Nurunisa; Li, Xiaoping; Asai, Yukako; Nist-Lund, Carl; Kurima, Kiyoto; Derfler, Bruce; György, Bence; Limapichat, Walrati; Walujkar, Sanket; Wimalasena, Lahiru N.; Sotomayor, Marcos; Corey, David P.; Holt, Jeffrey R.

doi:10.1016/j.neuron.2018.07.033

Cited by 283 publications

(391 citation statements)

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“…We have characterized the fast adaptation of hair cell MET channels containing different TMC proteins, which are considered to be a molecular component of the channel (Kawashima et al 2011;Pan et al 2013;Pan et al 2018). Our results indicate that both the extent and time constant of adaptation depend on which TMC isoform is present, with the observations effectively localizing the adaptation mechanism to the channel complex.…”

Section: Discussionmentioning

confidence: 89%

“…A mutation harboring a single amino acid replacement, D569N, in TMC1 had MET channels showing adaptation of comparable or greater extent compared to wild-type TMC1 channels, although with substantially smaller Ca 2+ permeability. According to prevailing models of TMC1, the D569 residue lies near the inner end of the hypothetical ion-conducting pore of the channel (Ballesteros et al 2018;Pan et al 2018), which might account for the effect on Ca 2+ permeability. These conflicting experimental findings raise concerns about the role of Ca 2+ entry in adaptation, echoing previous conclusions (Peng et al 2013;Peng et al 2016).…”

Section: Discussionmentioning

confidence: 99%

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The contribution of TMC1 to adaptation of mechanoelectrical transduction channels in cochlear outer hair cells

Goldring

Beurg

Fettiplace

2019

The Journal of Physiology

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Key points Hair cell mechanoelectrical transducer channels are opened by deflections of the hair bundle about a resting position set by incompletely understood adaptation mechanisms. We used three characteristics to define adaptation in hair cell mutants of transmembrane channel‐like proteins, TMC1 and TMC2, which are considered to be channel constituents. The results obtained demonstrate that the three characteristics are not equivalent, and raise doubts about simple models in which intracellular Ca2+ regulates adaptation. Adaptation is faster and more effective in TMC1‐containing than in TMC2‐containing transducer channels. This result ties adaptation to the channel complex, and suggests that TMC1 is a better isoform for use in cochlear hair cells. We describe a TMC1 point mutation, D569N, that reduces the resting open probability and Ca2+ permeability of the transducer channels, comprising properties that may contribute to the deafness phenotype. Abstract Recordings of mechanoelectrical transducer (MET) currents in cochlear hair cells were made in mice with mutations of transmembrane channel‐like (TMC) protein to examine the effects on fast transducer adaptation. Adaptation was faster and more complete in Tmc2–/– than in Tmc1–/–, although this disparity was not explained by differences in Ca2+ permeability or Ca2+ influx between the two isoforms, with TMC2 having the larger permeability. We made a mouse mutation, Tmc1 p.D569N, homologous to a human DFNA36 deafness mutation, which also had MET channels with lower Ca2+‐permeability but showed better fast adaptation than wild‐type Tmc1+/+ channels. Consistent with the more effective adaptation in Tmc1 p.D569N, the resting probability of MET channel opening was smaller. The three TMC variants studied have comparable single‐channel conductances, although the lack of correlation between channel Ca2+ permeability and adaptation opposes the hypothesis that adaptation is controlled simply by Ca2+ influx through the channels. During the first postnatal week of mouse development, the MET currents amplitude grew, and transducer adaptation became faster and more effective. We attribute changes in adaptation partly to a developmental switch from TMC2‐ to TMC1‐ containing channels and partly to an increase in channel expression. More complete and faster adaptation, coupled with larger MET currents, may account for the sole use of TMC1 in the adult cochlear hair cells.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

The contribution of TMC1 to adaptation of mechanoelectrical transduction channels in cochlear outer hair cells

Goldring

Beurg

Fettiplace

2019

The Journal of Physiology

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“…a, The hair-cell stereocilia bundle and mechanotransduction complex. The mechanotransduction complex is shown with a single dimeric tip-link filament connecting to a dimeric transduction channel 56 . b, Single-bond fusion proteins containing one EC1-2 binding domain.…”

Section: Main Textmentioning

confidence: 99%

The Dynamic Strength of the Hair-Cell Tip Link Reveals Mechanisms of Hearing and Deafness

Mulhall

Ward

Yang

et al. 2019

Preprint

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Our senses of hearing and balance rely on the extraordinarily sensitive molecular machinery of the inner ear to convert deflections as small as the width of a single carbon atom 1,2 into electrical signals that the brain can process 3 . In humans and other vertebrates, transduction is mediated by hair cells 4 , where tension on tip links conveys force to mechanosensitive ion channels 5 . Each tip link comprises two helical filaments of atypical cadherins bound at their N-termini through two unique adhesion bonds 6-8 . Tip links must be strong enough to maintain a connection to the mechanotransduction channel under the dynamic forces exerted by sound or head movement-yet might also act as mechanical circuit breakers, releasing under extreme conditions to preserve the delicate structures within the hair cell. Previous studies have argued that this connection is exceptionally static, disrupted only by harsh chemical conditions or loud sound 9-12 . However, no direct mechanical measurements of the full tip-link connection have been performed. Here we describe the dynamics of the tiplink connection at single-molecule resolution and show how avidity conferred by its double stranded architecture enhances mechanical strength and lifetime, yet still enables it to act as a dynamic mechanical circuit breaker. We also show how the dynamic strength of the connection is facilitated by strong cisdimerization and tuned by extracellular Ca 2+ , and we describe the unexpected etiology of a hereditary human deafness mutation. Remarkably, the connection is several thousand times more dynamic than previously thought, challenging current assumptions about tip-link stability and turnover rate, and providing insight into how the mechanotransduction apparatus conveys mechanical information. Our results reveal fundamental mechanisms that underlie mechanoelectric transduction in the inner ear, and provide a foundation for studying multi-component linkages in other biological systems.

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“…For signal termination, a cGMP-specific phosphodiesterase (PDE5) (Su & Vacquier, 2006) breaks down cGMP and, finally, a Na + /Ca 2+ -K + exchanger (NCKX) (Su & Vacquier, 2002) and/or a plasma membrane Ca 2+ -ATPase (PMCA) (Gunaratne et al, 2006) restore resting Ca 2+ levels. Mass spectrometric (MS) analysis of purified flagella from A. punctulata sperm identified all previously known signaling components, but also additional proteins that might be involved in the signaling pathway (Appendix Table S1): (i) the Ca 2+ -activated Cl À channel TMEM16 of olfactory cilia, which has been predicted to exist in sperm from pharmacological and modeling studies (Guerrero et al, 2013;Espinal-Enriquez et al, 2017); (ii) a dual-specific PDE10 that, unlike PDE5, can also hydrolyze cAMP, and, together with sAC, may control cAMP metabolism; (iii) K + /Cl À co-transporters KCC1 (SLC12A4) and/or KCC3 (SLC12A5); (iv) a Na + /HCO 3 À co-transporter (SLC4A11); (v) a sperm-specific Na + /K + -ATPase a subunit; and (vi) two members (TMC 5 and 7) of a mechano-sensitive channel family (Zhao & Müller, 2015;Pan et al, 2018). Sperm respond to mechanical stimulation with a Ca 2+ response (Kambara et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Absolute proteomic quantification reveals design principles of sperm flagellar chemosensation

et al. 2019

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Cilia serve as cellular antennae that translate sensory information into physiological responses. In the sperm flagellum, a single chemoattractant molecule can trigger a Ca2+ rise that controls motility. The mechanisms underlying such ultra‐sensitivity are ill‐defined. Here, we determine by mass spectrometry the copy number of nineteen chemosensory signaling proteins in sperm flagella from the sea urchin Arbacia punctulata. Proteins are up to 1,000‐fold more abundant than the free cellular messengers cAMP, cGMP, H+, and Ca2+. Opto‐chemical techniques show that high protein concentrations kinetically compartmentalize the flagellum: Within milliseconds, cGMP is relayed from the receptor guanylate cyclase to a cGMP‐gated channel that serves as a perfect chemo‐electrical transducer. cGMP is rapidly hydrolyzed, possibly via “substrate channeling” from the channel to the phosphodiesterase PDE5. The channel/PDE5 tandem encodes cGMP turnover rates rather than concentrations. The rate‐detection mechanism allows continuous stimulus sampling over a wide dynamic range. The textbook notion of signal amplification—few enzyme molecules process many messenger molecules—does not hold for sperm flagella. Instead, high protein concentrations ascertain messenger detection. Similar mechanisms may occur in other small compartments like primary cilia or dendritic spines.

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TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells

Cited by 283 publications

References 84 publications

The contribution of TMC1 to adaptation of mechanoelectrical transduction channels in cochlear outer hair cells

The contribution of TMC1 to adaptation of mechanoelectrical transduction channels in cochlear outer hair cells

The Dynamic Strength of the Hair-Cell Tip Link Reveals Mechanisms of Hearing and Deafness

Absolute proteomic quantification reveals design principles of sperm flagellar chemosensation

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