Transcript III Sensory - Washington State University

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®)
Gentamicin (Garamycin®)
Kanamycin (Kantrex®)
Neomycin (Mycifradin®)
Netilmicin (Netromycin®)
Paromomycin (Humatin®)
Streptomycin
Tobramycin (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.