Edited by: Bernd Fritzsch, University of Iowa, United States
Reviewed by: Gregory I. Frolenkov, University of Kentucky, United States; Régis Nouvian, INSERM U1051 Institut des Neurosciences de Montpellier, France
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Hair cells in the inner ear convert mechanical stimuli provided by sound waves and head movements into electrical signal. Several mechanically evoked ionic currents with different properties have been recorded in hair cells. The search for the proteins that form the underlying ion channels is still in progress. The mechanoelectrical transduction (MET) channel near the tips of stereociliary in hair cells, which is responsible for sensory transduction, has been studied most extensively. Several components of the sensory mechanotransduction machinery in stereocilia have been identified, including the multi-transmembrane proteins tetraspan membrane protein in hair cell stereocilia (TMHS)/LHFPL5, transmembrane inner ear (TMIE) and transmembrane channel-like proteins 1 and 2 (TMC1/2). However, there remains considerable uncertainty regarding the molecules that form the channel pore. In addition to the sensory MET channel, hair cells express the mechanically gated ion channel PIEZO2, which is localized near the base of stereocilia and not essential for sensory transduction. The function of PIEZO2 in hair cells is not entirely clear but it might have a role in damage sensing and repair processes. Additional stretch-activated channels of unknown molecular identity and function have been found to localize at the basolateral membrane of hair cells. Here, we review current knowledge regarding the different mechanically gated ion channels in hair cells and discuss open questions concerning their molecular composition and function.
Hair cells of the inner ear are specialized mechanosensory cells, which convert mechanical stimuli provided by sound waves (cochlea) or head movement (vestibular system) into electrical signals. Hair cells are highly polarized cells with extraordinary morphological specialization for sensing mechanical stimuli. The most prominent morphological specialization of a hair cell is the hair bundle. It protrudes from the apical surface of a hair cell and is formed by an array of F-actin based stereocilia that are arranged in a staircase of decreasing heights (Figure
Mechanically gated ion channels in hair cells.
Mechanotransduction currents measured with stiff probe or fluid jets.
Besides the sensory MET channels at tip links, a second mechanically activated channel was recently identified in hair cells that is located at their apical cell surface where stereocilia emanate from the cell body (Figures
Hair cells in the mammalian cochlea come in two flavors, outer hair cells (OHCs) and inner hair cells (IHCs). OHCs have an important function in amplifying input sound signals while IHCs transmit sound information to the CNS (reviewed in Dallos,
In the following, we will summarize current knowledge regarding the properties and molecular composition of the various mechanically gated ion channels in hair cells.
The activity of the sensory MET channel at the tips of stereocilia can be recorded in organotypic culture as an inward current following deflection of the hair bundle with a stiff probe (Figures
The MET channel is non-selective for cations (Corey and Hudspeth,
The organ of Corti in mammals has the ability to separate sound frequencies along its length—high-frequency tones at the proximal end and low-frequency at the distal end of the organ. The Ca2+ selectivity and single-channel conductance also show tonotopic characteristics in OHCs but not in IHCs. In 20 μM external Ca2+, single-channel conductance varies from 145 to 210 pS for OHCs along the tonotopic axis but is about 260 pS for IHCs along the entire length of the cochlea (Beurg et al.,
Sensory MET channels in hair cells adapt to mechanical stimuli, which leads to a decrease in current during a constant stimulus but additional stimulation again increases current. Adaptation is thought to set the resting tension of the transduction channel to position the channel near the most sensitive point of activation, and is important for providing amplification for mechanical signals (reviewed in LeMasurier and Gillespie,
During the early development of hair cells, their hair bundles are less directionally sensitive. Transducer currents can be observed by deflection of the hair bundle both towards the shortest and longest stereocilia (Waguespack et al.,
Several studies identified stretch activated MET currents in the basolateral membrane of hair cells, but the properties of these currents differed between reports. At least three different currents that are affected by mechanical force have been reported in OHCs. One type of current was activated by stretch and a single-channel conductance of 38–50 pS was determined for the underlying channel. This ion channel was non-selective to cations and had a reversal potential ~ −12 mV (Ding et al.,
The search for the molecular constituents of the MET channel in stereocilia has been in progress for decades. Using high speed Ca2+ imaging, it was demonstrated that the sensory MET channel is localized near the lower end of tip links (Beurg et al.,
Model of the sensory transduction channel and for PIEZO2.
Candidate components of the mechanotransduction channel in hair cells and how they affect channel activity.
Candidates | Stereocillia localization | MET requirement | Channel properties changed in mutant mice | Heterologous expression | |||
---|---|---|---|---|---|---|---|
Rise time | Adaptation | Single-channel conductance | Calcium permeability | ||||
TMC1/2 | Yes | Required | N/A | Slower | Conflict | Altered | Intracellular |
LHFPL5 | Yes | Required | Slower | Slower | Reduced | N/D | Cell surface together with Pcdh15 |
TMIE | Yes | Required | N/A | N/A | N/A | N/A | Cell surface |
However, whether TMC1 and TMC2 form the channel pore is still under debate. It was proposed that the tonotopic gradient in the conductance and Ca2+ selectivity of the MET channel can be explained by variations in the stoichiometry of TMC1/2 (Pan et al.,
TMHS/LHFPL5 is a second protein that has been implicated to be an integral component of the mechanotransduction channel in hair cells. TMHS/LHFPL5 is a member of a small subfamily within the large superfamily of proteins with four transmembrane domains (Petit et al.,
TMIE is a protein with two transmembrane domains and linked to deafness in both human and mice (Mitchem et al.,
The similarities in single-channel conductance and pharmacological properties of the normal and reverse-polarity current in hair cells initially suggest that these two mechanically gated currents are carried by the same channel pore (Kim et al.,
We still know next to nothing about the molecular composition of ion channels that carry the stretch activated currents in the basolateral membrane of OHCs (Ding et al.,
Recent studies have provided compelling evidence that hair cells express several molecularly distinct ion channels with different function. The best studied of these is the sensory MET channel at tips of stereocilia. Substantial evidence suggests that TMC1/2, TMHS and TMIE are integral components of the sensory MET channel (Figure
XQ and UM wrote the manuscript. Figures were designed by XQ.
UM is a co-founder of Decibel Therapeutics. The other author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.