Mechanisms of Transduction and Excitation in the Cochlea
The stereocilia on hair cells are composed of tightly packed actin filaments, bonded by a number of proteins which give them considerable rigidity. Their rootlets insert into the cuticular plate, also composed of actin filaments though with a less regular organization. The stereocilia in a bundle are cross-linked so that the whole bundle tends to move together when the stereocilia are deflected.
Links of one class, the tip links, emerge from the tips of the shorter stereocilia in the bundle to join to the side of the adjacent taller stereocilium. Tip links are composed of cadherin-23 and protocadherin-15. Deflection of the sterocilia n the excitatory direction (towards the tallest stereocilia) pulls on the tip links and pulls open the mechanotransducer channels by a direct mechanical action.
The molecular identity of the mechanotransducer channel is not known. It is possible that the channels are a member of the TRP (transient receptor potential) family.
Ca2+ imaging shows that the mechanotransducer channels are situated at or near the tips of the shorter stereocilia on the bundle, likely to be in association with the lower ends of the tip lin. Mechanotransduciton also depends on the integrity of the tip links, since it disappears if the links are broken by the removal of Ca2+ from around the bundle with chelators.
The single channel conductance is 145-260pS. The channel is a non-specific cation channel, with a pore diameter of around 1.2nm. We therefore expect mechanotransducer currents to be carried by K+ and to a lesser extent by Ca2+.
Electrophysiological analysis shows that the channels open with a very short delay (20 usec) and with a low temperature dependence, consistent with channel activation is undertaken in the framework of gating spring theory., in which the channel opens and closes under the influence of thermal energy pulled open by an elastic spring. Depending on the number of channel states that are chosen and their relative energies, realistic input-output functions for channel opening as a function of stereocilar deflection can be obtained. The functions are derived from the Boltzmann distribution. The gating spring may be formed by an elastic protein associated with the tip link or with the proteins that anchor the mechanotrasducer channel to the underlying cytoskeleton.
Hair cells adapt, that is shift their operating range, in response to sustained stimuli. Fast adaptation depends on the molecular reorganization within the mechanotransducer channels following the entry of Ca2+ while slow adaptation depends on the myosin-based motility of the upper insertion point of the tip link.
Sharp tuning in the cochlea depends on the active mechanical amplification of the traveling wave by the outer hair cells. The theoretical necessity for the amplification can be shown by mathematical analysis, which shows that experimentally obtained response patterns can be ontained only if there is an input of energy into the traveling wave, in a restricted region on the rising part of the traveling wave.
Outer hair cells put energy in to the traveling wave. The involvement of outer hair cells is shown by manipulations that affect the outer hair cells, which also affect the magnitude and sharp tuning of the mechanical traveling wave.
The production of energy by the hair cells has been shown by the existence of cochlear emissions, when the cochlea, either spontaneously or in response to acoustic stimulation, emits sound. The emissions depend on the integrity of the outer hair cells, Isolated outer hair cells generate two forms of motility, one depending on thength changes in the cell body driven by the protein prestin in the cell body, and the other depending on motility in the mechanotransducer apparatus, perhaps linked to the adaptation mechanism.
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Links of one class, the tip links, emerge from the tips of the shorter stereocilia in the bundle to join to the side of the adjacent taller stereocilium. Tip links are composed of cadherin-23 and protocadherin-15. Deflection of the sterocilia n the excitatory direction (towards the tallest stereocilia) pulls on the tip links and pulls open the mechanotransducer channels by a direct mechanical action.
The molecular identity of the mechanotransducer channel is not known. It is possible that the channels are a member of the TRP (transient receptor potential) family.
Ca2+ imaging shows that the mechanotransducer channels are situated at or near the tips of the shorter stereocilia on the bundle, likely to be in association with the lower ends of the tip lin. Mechanotransduciton also depends on the integrity of the tip links, since it disappears if the links are broken by the removal of Ca2+ from around the bundle with chelators.
The single channel conductance is 145-260pS. The channel is a non-specific cation channel, with a pore diameter of around 1.2nm. We therefore expect mechanotransducer currents to be carried by K+ and to a lesser extent by Ca2+.
Electrophysiological analysis shows that the channels open with a very short delay (20 usec) and with a low temperature dependence, consistent with channel activation is undertaken in the framework of gating spring theory., in which the channel opens and closes under the influence of thermal energy pulled open by an elastic spring. Depending on the number of channel states that are chosen and their relative energies, realistic input-output functions for channel opening as a function of stereocilar deflection can be obtained. The functions are derived from the Boltzmann distribution. The gating spring may be formed by an elastic protein associated with the tip link or with the proteins that anchor the mechanotrasducer channel to the underlying cytoskeleton.
Hair cells adapt, that is shift their operating range, in response to sustained stimuli. Fast adaptation depends on the molecular reorganization within the mechanotransducer channels following the entry of Ca2+ while slow adaptation depends on the myosin-based motility of the upper insertion point of the tip link.
Sharp tuning in the cochlea depends on the active mechanical amplification of the traveling wave by the outer hair cells. The theoretical necessity for the amplification can be shown by mathematical analysis, which shows that experimentally obtained response patterns can be ontained only if there is an input of energy into the traveling wave, in a restricted region on the rising part of the traveling wave.
Outer hair cells put energy in to the traveling wave. The involvement of outer hair cells is shown by manipulations that affect the outer hair cells, which also affect the magnitude and sharp tuning of the mechanical traveling wave.
The production of energy by the hair cells has been shown by the existence of cochlear emissions, when the cochlea, either spontaneously or in response to acoustic stimulation, emits sound. The emissions depend on the integrity of the outer hair cells, Isolated outer hair cells generate two forms of motility, one depending on thength changes in the cell body driven by the protein prestin in the cell body, and the other depending on motility in the mechanotransducer apparatus, perhaps linked to the adaptation mechanism.
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