III Sensory Hair Cell Transduction Mechanisms that underlie Hearing and Equilibrium

This is another very ancient sensory system, with roots in the earliest animals… Turning a mechanical stimulus into an electrical signal is something that is happening when a Paramecium moves through the debris of pond water, bumping into this and that, backing up and taking another direction. A mechanical stimulus is potentially a threat. Speed of response requires that mechanical distortion be transduced by mechanical linkage to ion channels. This does not rule out additional effects of the mechanical stimulation that modulates the response properties of channels or even activates genes, but the principal transduction mechanism is to modify the open/closed state of a channel.

The importance of understanding the Auditory System: 30 million Americans have significant hearing impairment. Damage from many kinds of insults gradually deprive us of acute hearing, and 25% of those over 60 years old suffer hearing loss. Understanding vertebrate hearing has been difficult because the small, modified epithelial cells are few in number and relatively inaccessible. The breakthroughs in understanding mechanisms of transduction have come from analyzing invertebrate systems and then looking for similarities.

Comparative Mechanotransduction Information on mechanisms of mechanotransduction have come from invertebrates, in which the genes were first discovered; subsequently, genes with homologous sequences were found in the vertebrates. Basic features that have been discovered are 1.a channel that detects movement of an external structure 2.A link to a channel that is anchored to the cell’s internal structure, the cytoskeleton. (Deformation of the skin could be an example.)

Basic idea of how mechanoreceptors work:

The nematode Caenorhabditis elegans has few cells and simple behaviors, a defined genome, and rapid generation time for evaluating mutants. It has 6 mechanoreceptors with the structure shown below:

The microtubules (arrow) are the intracellular anchor; all the genes for the structures were discovered in mutant worms

Relevance of these studies to mammals: Some C. elegans mutations, those of proteins of the linkage system, cause defective hearing in mice. The channel that operates in mechanodetection is an epithelial-type Na + channel and mice with mutations in that gene do not survive development.

Drosophila is a well-known genetic model with plenty of bristles specialized for mechanotransduction: (The mutant mechanoreceptor flies were also deaf!)

Drosophila mechanotransduction and some of the genes that produce the transduction proteins: note that there are two channels – adaptation is a feature of more advanced systems.

Similarities between invertebrate and vertebrate mechanoreceptors … Mechanotransduction channels in invertebrates and vertebrates open within microseconds – this is evidence that they are not regulated by second messengers but rather involve direct control of channels. Adaptation is a feature of all mechanosensory systems. It can involve the channels or the stiffness of the “spring” link.

Similarity of mechanoselective channels The channel is a non-selective cation channel; it is blocked by aminoglycoside antibiotics, which, in mammals, are potentially ototoxic. Examples: Amikacin (Amikin®) GentamicinGentamicin (Garamycin®) Kanamycin (Kantrex®) NeomycinNeomycin (Mycifradin®) Netilmicin (Netromycin®) Paromomycin (Humatin®) Streptomycin TobramycinTobramycin (TOBI Solution®, TobraDex®, Nebcin®)

Other similarities: The mechanoreceptor cells of worms and flies are ciliated cells, with a true kinocilium In “hair cells”, the receptor cells of the hearing and vestibular systems of vertebrates, a kinocilium is present in the vestibular apparatus cells (shown below). In hair cells, it is present during the development of the auditory hair cells.

The vestibular and auditory receptor systems are located in the membranous labyrinth – the inner ear

Classic view of the wave with frequencies localized on uncoiled basilar membrane – the “place” principle of frequency coding.

Relationship between the inner and outer hair cells and the tectorial membrane

Efferent and Afferent Connections in the Organ of Corti: Efferent connections take CNS commands to the periphery; afferent connections send sensory information to the CNS

Shearing forces operating in the cochlea

External clues to the transduction mechanism: A single hair cell’s cilia and the tip links that turn movement of the cilia into changes in the cell’s channels.

View of transduction system: the tip links bridge the extracellular space between the cilia, linking the anchored channels; the adaptation motor maintains the optimal tension for transduction.

Hair Cell Responses a) At rest,10% of the channels are open, resulting in some vesicle release, and activation of a few action potentials in the primary sensory neuron. b) deflection in one direction opens more channels, increasing vesicle release, and leading to a higher firing rate. c) deflection in the other direction closes some of the channels open at rest, reducing the number of action potentials generated.

Role of the Outer Hair Cells The outer hair cells, 75% of the population, are not the main sensory cells – they are associated with 5% of the afferent neurons. They transduce sound energy, however, but they turn it into mechanical force (they can push or pull) to alter the cell stiffness in relation to the tectorial membrane in the region where the sound wave is also affecting the inner hair cells. This is a mechanical tuning that is stimulated by the vibration energy; it increases the capacity to discriminate pitch. If this class of hair cells is selectively destroyed, hearing, especially frequency discrimination, is lost. They receive innervation (an efferent pathway) that modifies their responses. The ability to “focus” on one person’s voice in a noisy room involves selective increases in acuity due to alterations in the outer hair cell’s responses in one region of the basilar membrane.