Mechanically Gated Ion Channels in Mammalian Hair Cells

Abstract

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.

Keywords: LHFPL5; PIEZO2; TMC1; TMIE; auditory; hair cell; inner ear; mechanotransduction.

Figure 1

Mechanically gated ion channels in hair cells. (A) Diagram of a hair cell with the sensory channel located at the tips of the shorter stereocilia, reverse-polarity channel in the apical cell surface and stretch-activated channels in the basolateral membrane. (B) The sensory transduction channel is localized near the lower end of tip links, which consists of PCDH15 and CDH23. (C) The reverse-polarity channel is concentrated near the base of the longest stereocilia. (D) Basolateral currents carried by unknown channels. Cl⁻ influx through basolateral channel may drive motor protein prestin transitions.

Figure 2

Mechanotransduction currents measured with stiff probe or fluid jets. (A) Representative transduction currents in outer hair cells (OHCs) in response to a set of 10 ms hair bundle deflections with a stiff probe ranging from −400 nm to 1000 nm with 100 nm steps. (B) Representative plot of open probability with hair bundle deflection from (A), fitted with a three Boltzmann model. (C) Representative mechanotransduction currents in response to sinusoidal deflection of hair bundles at P5 for a wild-type C57BL/6 mouse with and without BAPTA treatment to break tip links. Stimulus monitor, the driving voltage to the fluid jet, is shown at the top. A positive driving voltage denotes displacement toward the tallest edge of the hair bundle. In controls the response after BAPTA treatment occurs in the opposite phase (reverse-polarity) of the stimulus compared to the response prior to BAPTA treatment.

Figure 3

Model of the sensory transduction channel and for PIEZO2. (A) Transmembrane channel-like proteins 1 and 2 (TMC1/2), tetraspan membrane protein in hair cell stereocilia (TMHS)/LHFPL5 and transmembrane inner ear (TMIE) bind to PCDH15 and are constituents of the sensory mechanoelectrical transduction (MET) machinery. TMC1/2 and TMHS/LHFPL5 bind to PCDH15. TMIE binds to TMHS/LHFPL5 as well as to the unique C-terminal domain of one specific PCDH15 isoform in stereocilia. (B) Model of the PIEZO2 channel, which contain at least 18 transmembrane domains and potentially up to 38 transmembrane domains.