In this second lecture, we continued our genetic dissection of the mechano-electrical transduction machinery, focusing on the search for the mechano-electrical transduction channel (or MET channel). The first questions that arose concerning this channel were those of its localization, the number of channels per sensory cell and per stereocil, and then its pharmacological and biophysical characteristics. The location of the MCT channel was first determined, rather crudely and indirectly, by electrophysiological measurements, then more directly and precisely using optical methods, namely calcium imaging. In addition, increasingly precise measurements of the currents activated when the ciliary tuft is deflected have led to an estimate of the number of channels per stereocil and a detailed analysis of their properties within the framework of the gating spring model. To this day, however, the molecular identity of this channel remains largely unknown. Candidates have come and gone, but some remain valid. The search for the components of the MCT channel needs to be placed in the broader context of current knowledge of mechanically-activated ion channels, whose identification has accelerated in recent years and whose activation mechanisms have, for some of them, been discovered.
We retraced the "saga" of the search for the MCT channel, recalling its various stages, which include a number of "failed attempts". We then focused on transmembrane proteins, now considered the best candidates to belong to the MCT channel, or more broadly to the molecular complex of which this channel is a part. We have reviewed each of the proposed candidates in turn, namely TMHS (tetraspan membrane protein of hair cell stereocilia), TMIE (transmembrane inner ear expressed protein), and TMC1/TMC2 (transmembrane channel-like protein 1/2), all encoded by deafness genes, pointing to recent evidence supporting the hypothesis of their involvement in the TME machinery. These are essentially based on the study of mice in which the corresponding gene has been inactivated. It now seems well established that TMC1 and TMC2 are closely linked to the TME channel; these proteins could either form an auxiliary subunit or enter into the composition of the channel pore. Nevertheless, we have highlighted the difficulties that remain in validating the involvement of these candidates in the MCT channel, the most pressing of which is to demonstrate that these proteins behave as mechanosensitive channels in heterologous cellular expression systems. On the other hand, at any given moment, a deafness gene may arise, encoding a protein that better meets the criteria of a "best candidate" than the TMC proteins. Clearly, the end of the saga is yet to be written, and may yet prove rich in surprises.
