Who needs tip links? Backwards transduction by hair cells

The molecular identity of the channel that mediates mechanotransduction by hair cells remains uncertain, despite being biophysically characterized since the late 1970s (Corey and Hudspeth, 1979). Two recent reports from Jeffrey Holt, Gwenaelle Géléoc, Andrew Griffith, and their colleagues suggested that the hair cell’s transduction channel is made up of members of the transmembrane channel (TMC)-like family of membrane proteins (Kawashima et al., 2011; Pan et al., 2013) (Fig. 1 A). They showed that the TMC paralogs TMC1 and TMC2 are selectively expressed in the inner ear, appearing at the onset of transduction, and that at least one of them must be expressed for normal mechanotransduction. In this issue of the JGP, Robert Fettiplace and colleagues (Kim et al.) challenge the Holt–Géléoc–Griffith model, suggesting instead that the TMCs do not make up the transduction channel but instead couple those channels to tip links, the mechanical elements that impart directional sensitivity to hair cells. Examining transduction in a Tmc1;Tmc2 double mutant, they found persistence of a conductance with properties very similar to those of the transduction channel, except that it is activated by mechanical deflections of the opposite polarity. This surprising result raises the possibility that the transduction channel is a membrane protein distinct from TMC1 and TMC2 that only becomes functional as the transduction channel once other key molecules, like the TMCs and tip-link cadherins, are expressed. Nevertheless, a few reservations remain about this interpretation, and the conclusions are not as clear-cut as Kim et al. (2013) imply. In wild-type hair cells, the transduction channel is located in the hair bundle, the mechanically sensitive structure decorating the apical surface of the cell. The bundle is composed of a single asymmetrically located kinocilium, an axonemal cilium, as well as dozens of actin-filled stereocilia arranged in rows of increasing height. External stimuli like sound deflect the bundle, which leads to the opening of transduction channels when the deflection is toward the taller stereocilia, referred to as a positive stimulus. Many biophysical features of the channel are known (Gillespie and Müller, 2009); for example, it is a nonselective cation channel (reversal potential near zero under normal ionic conditions),