Question

Neuroscience

1. The net current flowing through an ion channel at a cell’s resting potential flows in one direction determined by the equilibrium potentials for the ions that flow through it. Given this, how is it possible for a hair cell in the inner ear to alternately hyperpolarize and depolarize during sound waves when they only have a single mechanosensitive ion channel (TMC1/TMC2 heteromer)?

Answer 1

Sensory transduction in auditory and vestibular hair cells requires expression of transmembrane channel-like (Tmc) 1 and 2 genes, but the function of these genes is unknown. To investigate the hypothesis that TMC1 and TMC2 proteins are components of the mechanosensitive ion channels that convert mechanical information into electrical signals, we recorded whole-cell and single-channel currents from mouse hair cells that expressed Tmc1, Tmc2, or mutant Tmc1. Cells that expressed Tmc2 had high calcium permeability and large single-channel currents, while cells with mutant Tmc1 had reduced calcium permeability and reduced single-channel currents. Cells that expressed Tmc1 and Tmc2 had a broad range of single-channel currents, suggesting multiple heteromeric assemblies of TMC subunits. The data demonstrate TMC1 and TMC2 are components of hair cell transduction channels and contribute to permeation properties. Gradients in TMC channel composition may also contribute to variation in sensory transduction along the tonotopic axis of the mammalian cochlea.

All mutations are associated with dominant deafness DFNA36 and substitute a positively charged residue (lysine or arginine) or remove a negatively charged residue (aspartate), which may influence Ca 2+ binding within the channel pore. We shall focus on the properties of the mouse mutation Tmc1 p.D569N (25) and compare it with Tmc1 p.M412K, known as Beethoven (11,12,28,29), these being the sites in the mouse TMC1 homologous to the D572 and M418 human mutations. Both are semidominant mutations linked to progressive hearing loss, but they have subtly different effects on MET channel properties.

he sense of hearing is mediated by an extraordinarily intricate process in which hair cells convert mechanical forces from sound waves into electrical signals that are relayed to the brainAll vertebrate hair cells contain stereocilia bundles on their apical surface that are arranged in rows of increasing height and are connected to each other by small strands called tip links, Hair cells are positioned in the cochlea along a tonotopic gradient where the frequency of the sound waves detected varies from the apex to the base.Mechanical forces produced by sound waves deflect the hair cell stereocilia bundles and the physical strain induced by tip link movement is thought to gate a mechanically activated (or mechanotransducer, MT) ion channel located at the lower end of each tip.Tip links are thought to be essential for the gating of the ion channel and a number of genes have been described that are required for the proper connection of the tip link to the stereocilia at both the upper and lower ends. Although a number of candidate genes have been suggested, the identity of the mammalian mechanotransducer channel complex remains incomplete. At present, four genes have been shown to be necessary components of the hair cell mechanotransducer complex: Transmembrane Channel Like proteins 1 and 2 (TMC1 and TMC2), Tetraspan Membrane Protein of Hair Cell Stereocilia (TMHS), and Transmembrane Inner Ear Expressed Gene (TMIE).