The cloning of deafness genes, especially those for Usher syndrome, has

The cloning of deafness genes, especially those for Usher syndrome, has helped to identify a variety of structural proteins involved in the development and function of hair-cell stereocilia. used motor complexes located at the upper end of each tip link to constantly adjust the resting bias on these channels, thereby generating an adaptation to static stimuli (examined in [1]). This JNJ-26481585 inhibitor motor was composed of myosin-1c molecules that were regulated by Ca2+ entering through nearby transduction channels [2]. Open in a separate window Physique 1. Mechanotransduction in vertebrate hair cells (a) The hair bundle of each hair cell shows a JNJ-26481585 inhibitor graded increase in stereocilia heights (level = 1 m). Deflections toward the tallest stereocilia are excitatory, opening transduction channels near their suggestions. (b) A 170 nm tip link, composed of cadherin 23 and protocadherin 15, extends along the sensitive axis from the tip of each stereocilium to the side of its tallest neighbor (level = 100 nm). (c) When deflected, stereocilia remain touching at their suggestions but shear, so that excitatory deflections take action to tighten tip links. (d) A revised model for transduction supposes that ion channels at the lower end of each tip link are pulled open by tip-link tension. Tip links are attached to the actin cores of stereocilia by myosin-1c motor proteins at their upper ends and through mechanosensitive transduction channels at their lower ends. cdh23, cadherin 23; myo1c, myosin 1c; pcdh15, protocadherin 15. Five years ago, we knew even more: the tip link had been tentatively identified as cadherin 23 [3], the adaptation CCNE2 motor had been confirmed as myosin 1c by a chemical genetic strategy [4], and a strong candidate for the transduction channel itself, TRPA1 (transient-receptor-potential-like, ankyrin-containing ion channel 1), had been found [5]. It seemed there were just a few details to work out, and these had to do with how the motor, tip link, JNJ-26481585 inhibitor and channel were all connected. However, a flurry of new papers has shaken this view of hair-cell transduction in several fundamental ways. Major recent improvements First, it was found that TRPA1 is not an essential component of the transduction apparatus. TRPA1 is made by hair cells and does play an important regulatory role in the cochlea, but mechanotransduction itself is usually perfectly normal in mice lacking TRPA1 [6]. At the moment, you will find no JNJ-26481585 inhibitor other good channel candidates stepping forward for concern. Second, the tip link turned out to be more complex than imagined. A combination of exquisite immunogold and unfavorable stain electron microscopy [7] showed that the tip link is most likely a tetramer of cadherins: two parallel strands of cadherin 23 forming the upper two-thirds of the link and two parallel JNJ-26481585 inhibitor strands of protocadherin 15 forming the lower one-third (Physique 1d). This structure helps in understanding inherited hearing loss in that cadherin 23 and protocadherin 15 are both products of genes defective in the human Usher syndrome, a disorder characterized by congenital deafness and progressive blindness (Usher types 1D and 1F, respectively). However, the structure appears incompatible with earlier views of the transduction apparatus, in which the tip link functions as an elastic spring. First, the extracellular portions of these cadherins do not appear very stretchy in electron micrographs. Second, steered molecular dynamics simulations of cadherins [8] predict an elasticity much lower than that known from biophysical measurements to be associated with the transduction apparatus. There are now speculations about where that springiness might be [9]; for instance, there may be elastic.

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