How many proteins does it take to gate hair cell mechanotransduction?

Abstract

Components of the Mechanotransducer ComplexMechanosensory hair cells of the inner ear transduce sound or head motion into electrical signals through the gating of mechanically coupled ion channels. Although many cell types can respond to mechanical force (1), the disposition of mechanotransduction (MT) channels to the very tips of stereocilia (2, 3) confers onto hair cells of the inner ear their specialized sensitivity (4, 5). Differential deflection of the stereociliary tips is transmitted to the MT channels via extracellular "tiplinks" that extend between taller and shorter stereocilia (6-8). The tip-links are composed of cadherin 23 and protocadherin 15 (5), the latter of which forms the lower end coupled to the MT gating complex. Positional cloning of a human deafness locus identified transmembrane channel-like protein isoforms (TMC)1 and TMC2 as potential components of the MT complex (9). TMC1 and TMC2 interact with protocadherin 15 (10) and have been nominated as subunits of the channel itself (11), perhaps combining differentially to generate the tonotopic variation in unitary conductance (larger in higher frequency hair cells) (12). The challenge for the field is to establish molecular mechanisms in a cellular organelle (the hair bundle) that couples extracellular force to channel gating through a still incompletely defined complement of interacting proteins. The problem is compounded by the fact that the MT channel and its binding partners must be transported and assembled at the stereociliary tips. In PNAS, Beurg et al. (13) shine a revealing light onto these complexities. The authors show that LHFPL5 (lipoma HMGIC fusion partnerlike 5, also known as tetraspan membrane protein of hair cell stereocilia, or TMHS) is required for normal MT current, apparently by regulating the participation of TMC1 (but not TMC2). These results in themselves help to keep the story of haircell MT moving forward. However, the authors' description of "reverse-polarity" MT currents puts an intriguing twist into the plot. Reverse-Polarity MechanotransductionThe cornerstone of hair-cell MT is its directional specificity. Deflection toward the taller stereocilia causes MT channel opening, cationic influx, and hair-cell depolarization; the opposite motion causes channel closure (4). Incredibly, hair cells of homozygous LHFPL5 null (LHFPL5 −/− ) mice generate Beurg et al. propose that LHFPL5 is required for correct positioning of TMC1 in the MT complex, and in particular for the tonotopic gradient in unitary conductance of the MT channel.reverse-polarity MT currents that can be even larger than those for the normal polarity motion. Reverse-polarity currents also have been reported for TMC1/TMC2 double mutants (14) and other MT-disrupted hair cells (15), keeping open the nomination process for MT channel proteins. Knockout of LHFPL5 produced smaller single MT channel currents and flattened the tonotopic gradient in unitary conductance (for normal polarity motion, reverse-polarity currents appear similar in low-and high-frequency ha...

TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia

“…Association of TMC1 and TMC2 with other MET proteins to form a stable complex may explain TMC1 enrichment at stereocilia tips even after tip link disruption by BAPTA. Other proteins, such as PCDH15 and TMIE, which were recently shown to interact with TMC proteins (Beurg et al, 2015; Fuchs, 2015; Maeda et al, 2014) and TMHS/LHFPL5 identified as an MET channel accessory component (Xiong et al, 2012) may contribute to the spatiotemporal distribution of TMC1 and TMC2 in stereocilia. Similar to TMC, PCDH15 remains at stereocilia tips following BAPTA treat ment (Indzhykulian et al, 2013).…”

“…Aside from the tip link proteins, the molecular composition of the MET apparatus remains elusive (Fuchs, 2015; Gillespie et al, 2005). The tetraspanin TMHS/LHFPL5 (Beurg et al, 2015; Xiong et al, 2012) and a protein with two transmembrane domains, TMIE (Zhao et al, 2014), have recently been identified as MET channel accessory components.…”