Departments of 1 Otolaryngology and 2 Physiology and Biophysics, The University of Texas Medical Branch, Galveston, Texas 77555-1063
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ABSTRACT |
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Linopirdine and XE991, selective
blockers of K+ channels belonging to the KCNQ family, were
applied to hair cells isolated from gerbil vestibular system and to
hair cells in slices of pigeon crista. In type II hair cells, both
compounds inhibited a slowly activating, slowly inactivating component
of the macroscopic current recruited at potentials above 60 mV. The
dissociation constants for linopirdine and XE991 block were <5
µM. A similar component of the current was also blocked by 50 µM
capsaicin in gerbil type II hair cells. All three drugs blocked a
current component that showed steady-state inactivation and a
biexponential inactivation with time constants of ~300 ms and 4 s. Linopirdine (10 µM) reduced inward currents through the
low-voltage-activated K+ current in type I hair cells, but
concentrations up to 200 µM had little effect on steady-state outward
K+ current in these cells. These results suggest that KCNQ
channels may be present in amniote vestibular hair cells.
delayed rectifier; potassium channel; pigeon; gerbil
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INTRODUCTION |
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VESTIBULAR HAIR CELLS EXPRESS a wide variety of K+ channels that are thought to confer distinct filtering properties on specific cell types. Although the biophysical properties of these K+ channels have been characterized in type I and type II vestibular hair cells, little is known about their molecular structure (2, 4, 7, 11, 12, 15, 17, 18-21, 25-27, 36). All mature type I hair cells express a delayed rectifier conductance (gKI or gK,L), which can be active at unusually negative membrane potentials and shows little inactivation (2, 12, 20, 25-27). Type II cells form a more heterogeneous population and exhibit a number of K+ conductances with different activation and inactivation properties. Outward K+ currents in pigeon type II hair cells have been shown to consist of a rapid A-type conductance (gKA) sensitive to 4-aminopyridine (4-AP), a Ca2+-activated conductance [gK(Ca)], and a slowly activating, slowly inactivating delayed rectifier conductance (gKII) sensitive to external tetraethylammonium (11). The main outward conductance in mammalian type II hair cells is a 4-AP-sensitive delayed rectifier gK, but gK(Ca) and gKA have also been reported (4, 12, 19, 27). In pigeon vestibular epithelia, K+ conductances have a regional distribution: gKA predominates in type II cells of the peripheral crista and extrastriolar regions of the utricle, whereas cells in more central regions have slower kinetics owing to gKII (16, 36). A similar expression pattern was reported in the frog crista, where a delayed rectifier gK was the predominant conductance in central regions, and both gKA and gK were present in peripheral locations (17).
Recent studies have implicated the involvement of KCNQ channels in inner ear function (9, 10, 33). KCNQ1 subunits, together with the smaller subunit "minK," form a K+ channel in vestibular dark cells and marginal cells of the stria vascularis, which appears to be important for the maintenance of K+ levels in endolymph (33). KCNQ4 channels are expressed in outer hair cells of the mammalian cochlea, and a mutation in the KCNQ4 gene gives rise to a form of nonsyndromic deafness (10). Most recently, KCNQ4 channels have also been shown in type I hair cells and their associated calyx fibers with the use of antibodies to KCNQ4 (9). To investigate the functional presence of channels encoded by KCNQ genes in vestibular hair cells, we tested the effects of two known blockers of KCNQ channels on type I and type II hair cells from the pigeon and gerbil. Although we found a component of the macroscopic K+ current in type II hair cells with high sensitivity to KCNQ channel blockers and capsaicin, the kinetics of this current did not resemble those of previously described KCNQ currents. In type I hair cells, the resting conductance gKI was partially blocked by KCNQ channel blockers.
We conclude that the high sensitivity of a type II hair cell current to linopirdine and XE991 suggests the presence of KCNQ channels in these cells. The low sensitivity of the type I hair cell conductance to these blockers suggests that KCNQ1-3 are not involved but, together with recent molecular evidence, strongly suggests that KCNQ4 contributes to the resting current in type I hair cells.
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METHODS |
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Experimental procedures for animal treatment were approved by The University of Texas Medical Branch Animal Care and Use Committee and were within American Physiological Society and National Institutes of Health guidelines.
Isolation of gerbil vestibular hair cells.
Hair cells were nonenzymatically dissociated as described previously
(21). The semicircular canals and utricles were removed from Mongolian gerbils (35-65 g) under deep anesthesia
[pentobarbital sodium (Nembutal), 50 mg/kg ip, and ketamine, 40 mg/kg
im] and placed in a high-Mg2+, low-Ca2+
solution containing (in mM) 135 NaCl, 5 KCl, 10 MgCl2, 0.02 CaCl2, 2 NaH2HPO4, 8 Na2HPO4, and 3 D-glucose for 32 min
at 37°C. Tissue was then transferred to a solution of Leibovitz's
L-15 medium (Life Technologies) containing bovine albumin (1 mg/ml) for
50 min at room temperature. Hair cells were mechanically dissociated by drawing a probe across the surface of the epithelium immersed in
L-15 medium in the recording chamber and viewed on a Nikon inverted
microscope. Type I and type II vestibular hair cells were identified by
their neck-to-plate and neck-to-body ratios (24).
Preparation of pigeon vestibular slices. Slices were prepared as described previously (16, 36). Briefly, the semicircular canals and utricles were removed from deeply anesthetized (pentobarbital sodium, 40 mg/kg iv, supplemented with ketamine, 60 mg/kg im) white king pigeons (200-350 g) and kept at 37°C in DMEM (Life Technologies) supplemented with 24 mM NaHCO3, 15 mM PIPES, 50 mg/l ascorbate, and 1.5% FCS. End organs were embedded separately in agar and cut to a thickness of 150-200 µm using a Vibratome (Campden Instruments, Loughborough, UK). Individual slices were immobilized in the recording chamber with a weighted nylon mesh, viewed using differential interference contrast optics on a Zeiss Axioskop, and bathed with extracellular solution containing (in mM) 145 NaCl, 3 KCl, 15 HEPES, 1.0 MgSO4, 2.0 CaCl2, and 10 glucose and 50 mg/l ascorbate, with pH adjusted to 7.4 with NaOH.
Recording conditions. Electrodes were fabricated from capillary tubing (model PG165T, Warner Instrument, and model 1B150F-3, World Precision Instruments) using a microelectrode puller (model P-87; Sutter Instruments). Electrodes were coated with silicone elastomer (Sylgard, Dow Corning) or 5% silanizing solution, and the tips were polished on a microforge (model MF 83; Narashige). The electrode solution for recording from gerbil hair cells contained (in mM) 110 KF, 15 KCl, 27 KOH, 1 NaCl, 10 HEPES, 3 D-glucose, 1.8 MgCl2, and 10 EGTA, pH 7.4. For pigeon hair cell recordings, the electrode solution contained (in mM) 140 KCl, 10 HEPES, 2.0 MgCl2, 1.0 CaCl2, and 11 EGTA, with pH adjusted to 7.0 with KOH.
Conventional whole cell patch-clamp experiments were carried out at room temperature (20-22°C). Recordings from isolated hair cells were made with an Axopatch-1C patch amplifier connected to a personal computer through an analog-to-digital converter (model CED 1401; Cambridge Electronic Design). Data were acquired with Patch- and Voltage-Clamp software (version 6; Cambridge Electronic Design). Signals were filtered on-line at 2-5 kHz. The series resistance averaged 3.1 ± 0.5 (SD) MData analysis. Data were analyzed using the patch-clamp acquisition software described above and Sigmaplot (version 5.0; Jandel Scientific) and Origin (version 5.0; Microcal). No leak subtraction of records was performed. Values are means ± SD.
Chemicals and drugs. Stock solutions of linopirdine (Research Biochemicals) and XE991 (Dupont Pharmaceuticals, Wilmington, DE) were prepared in DMSO and 0.1 M HCl, respectively. Capsaicin was purchased from Sigma Chemical and dissolved in ethanol. The final concentration of DMSO or ethanol did not exceed 0.1%, and at this concentration, vehicles alone produced no significant change in the amplitude of outward currents in isolated type I and type II vestibular hair cells. 4-AP (Fluka) was added directly to the external solution. Solutions were applied to isolated gerbil cells via a series of flow pipes (380 µm ID) positioned close to the cell under study and removed by aspiration with a peristaltic pump. Solutions were applied to pigeon hair cell slices using a DAD superfusion system (ALA Scientific Instruments). The tip (100 µm ID) of the delivery electrode was placed ~50 µm from the target cell. Drugs were superfused onto the cell for 60 s before and during recordings. Drugs were washed off the cell by 180 s of superfusion with bath solution and exchange of the bath solution using a peristaltic pump (1 ml/min, bath volume 2 ml).
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RESULTS |
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KCNQ channel blockers reduce current in type II hair cells.
Outward currents in vertebrate type II hair cells have previously been
characterized as K+ selective with delayed rectifier,
A-type, and Ca2+-activated K+ channel
components (4, 11, 12, 15, 17, 18, 19, 27, 36). Figure
1 shows whole cell currents recorded from a dissociated type II gerbil semicircular canal hair cell in response to a series of depolarizing steps during control (Fig. 1A)
and during superfusion of 2 µM linopirdine (Fig. 1B). This
concentration was chosen initially, since previous results showed that
linopirdine was a selective blocker of the M current in hippocampal
neurons at <3 µM (30). Linopirdine reduced outward
currents, unmasking currents with activation and inactivation kinetics
that were faster than those of control (Fig. 1B). The
currents blocked by linopirdine, obtained by subtraction of currents in
the presence of linopirdine from control, are shown for three
depolarizing steps in Fig. 1C. Peak currents and currents
measured at the end of the 4-s pulse are shown in the current-voltage
plot of Fig. 1D for control and in the presence of
linopirdine. Current at 0.5 s into the pulse was
reduced by an average of 44.1 ± 7.9% (n = 8) by
2 µM linopirdine in gerbil type II hair cells.
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(1) |
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(2) |
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Capsaicin block of current in gerbil type II hair cells.
Capsaicin is reported to block a component of IK
with slow activation and inactivation kinetics in frog semicircular
canal hair cells (15). We also tested the effect of
capsaicin on currents in gerbil type II hair cells and found a block
similar to that produced by linopirdine and XE991 (Fig.
6A). As shown in Fig. 6A, the capsaicin-sensitive current, like the
linopirdine-sensitive current, inactivated with a double-exponential
time course. Values for 1 ranged from 330 to 664 ms and
values for
2 from 1.9 to 7.3 s over a range of
voltages in four cells studied. Figure 6B shows that a
combination of linopirdine and capsaicin produced a reduction in
current that was no greater than that produced by 10 µM linopirdine
alone. Similarly, no additional reduction in current was observed when
both capsaicin and linopirdine were applied to a cell after capsaicin
alone, suggesting that the two drugs blocked the same set of channels.
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Effects of KCNQ channel blockers on currents in type I vestibular
hair cells.
Figure 8 shows typical currents from a
type I gerbil hair cell before and during application of 10 µM
linopirdine. The large resting conductance is due to the presence of
the signature type I hair cell current, IKI
(20, 26). Linopirdine reduced inward currents and
instantaneous outward currents but had little effect on steady-state
outward currents (Fig. 8, B and C). The effects of linopirdine on control currents are compared with those of 0.5 mM
4-AP, a known blocker of IKI, in Fig.
8C. At 200 µM, linopirdine only slightly reduced
steady-state outward currents measured at 50 mV in pigeon and gerbil
type II hair cells (Fig. 8D). IKI is
the main contributor to the outward current at this potential (20, 26). In pigeon and gerbil type I hair cells, inward
currents were reduced by an average of 17.3 ± 16.6%
(n = 4) and 37.0 ± 23.9% (n = 6), respectively, in the presence of 200 µM linopirdine. XE991
had no effect on steady-state outward currents measured between
10
and 0 mV in gerbil type I hair cells at concentrations up to 10 µM in
six cells tested but reduced steady-state inward currents by an average
of 55 ± 30.9% (data not shown). Linopirdine and XE991 were
therefore not effective blockers of outward type I hair cell
IK but reduced inward currents through
IKI at hyperpolarized potentials. In addition,
capsaicin (50 µM) had no effect on voltage-dependent currents in two
gerbil type I hair cells tested.
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DISCUSSION |
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Are KCNQ channels expressed in type II vestibular hair cells?
In this work, we show that low concentrations of linopirdine and
XE991 block a slowly inactivating component of the delayed rectifier current (IK) in gerbil and pigeon type
II vestibular hair cells. At comparable concentrations, these drugs
have previously been characterized as selective inhibitors of
K+ channels belonging to the KCNQ family (30,
35). Five members of this gene family have been described:
KCNQ1, which associates with minK to form a slowly activating
IK (29, 33), KCNQ2 and KCNQ3, which
coassemble to form the M channel (35), KCNQ4, which underlies an IK in outer hair cells of the
mammalian cochlea (10, 14), and KCNQ5, which coassembles
with KCNQ3 and may also underlie certain types of M current
(13). The IC50 values for XE991 blockade of expressed KCNQ1, KCNQ2, and KCNQ2 + KCNQ3 channels were
reported to be <1 µM (35). This was at least an order
of magnitude less than values for a variety of other K+
channels expressed in oocytes (35). However, regulatory
-subunits can alter current kinetics as well as their sensitivity to
drugs. For example, coexpression of minK subunits with KCNQ1 produces channels that are less sensitive to drugs such as clofilium,
XE991, and the benzodiazepine R-L3 compared with KCNQ1
alone (28, 34, 37). Furthermore, species differences in
the sensitivity of the slowly activating IsK to lanthanum have been
reported (6).
Capsaicin-sensitive current in type II hair cells. The effect of capsaicin on gerbil type II hair cells was similar to that of linopirdine and XE991; i.e., it blocked an inactivating component of the outward current in gerbil type II hair cells. Capsaicin blocks a variety of IK, including Kv1.1, 1.2, 1.3, 1.5, and 3.1 (5), and was recently reported to block IC, the slowly inactivating component of IK in frog hair cells (15). Capsaicin activates a nonselective cation channel in sensory neurons that mediates a sustained inward current at hyperpolarized potentials (1). The properties of the capsaicin-sensitive current reported here are inconsistent with those of a cation current. Furthermore, the observation that linopirdine and a combination of linopirdine and capsaicin block the same current strongly suggests that the capsaicin effect is specific to the K+ channel in type II hair cells.
At least two channel types can now be defined as underlying the previously described 4-AP-sensitive IK in mammalian type II hair cells (27), one of which is sensitive to linopirdine, XE991, and capsaicin. IC in frog hair cells activated slowly (Regional variations and the linopirdine-sensitive current.
Across species, macroscopic currents in type II vestibular hair cells
have been broadly divided into two classes: those with rapid activation
and inactivation kinetics ("fast" cells) with a dominant
IA and those with slower kinetics ("slow"
cells) with a dominant IK (4, 11, 12, 17,
18, 23, 36). The different K+ channels underlying
these responses can be ascribed specific roles in the filtering of
vestibular signals. For example, in response to current injections, the
membrane potential of pigeon slow cells oscillated at lower frequencies
than the membrane potential of fast cells (36).
Furthermore, the quality of membrane resonance varied linearly with
frequency only in type II hair cells with slow inactivation in the
pigeon lagena (23). Our results suggest that the
linopirdine-sensitive current contributes preferentially to the
properties of slow cells. Because the zero-current potential for pigeon
and mammalian type II hair cells averages about 55 mV (11,
12), this current will only become substantially activated after
periods of hyperpolarization. The significance of the predominance of
the slower conductance in central locations of the crista and utricle
remains to be explored.
KCNQ channel blockers and type I hair cells. Type I hair cells have a low-voltage-activated K+ conductance, gKI, which bears some similarity to gK,n in outer hair cells. Both conductances are active at rest, show a characteristic deactivation on stepping to hyperpolarized potentials, are relatively insensitive to externally applied tetraethylammonium, and in mouse are first expressed a few days after birth (2, 8, 14, 20, 27). KCNQ4 subunits are required for IK,n, which was reported to be very sensitive to block by linopirdine (KD = 0.7 µM) (14). However, KCNQ4 channels expressed in oocytes were reportedly much less sensitive, with 200 µM linopirdine producing <40% block of the current (10). This discrepancy could be explained if KCNQ3, together with KCNQ4, underlies IK,n in outer hair cells. Although we observed a reduction in inward currents carried through IKI in type I hair cells in response to linopirdine, outward currents were relatively resistant to block by the drug at concentrations as high as 200 µM. Coupled with the recent localization of KCNQ4 in the membranes of type I hair cells and calyces (9) and the relative insensitivity of KCNQ4 to linopirdine, these results suggest that KCNQ4 channels contribute to the resting conductance in type I vestibular hair cells.
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ACKNOWLEDGEMENTS |
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We thank Brett Pirtle for technical assistance and Dr. Barry S. Brown for the gift of XE991.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants DC-03287 (to K. J. Rennie) and DC-01273 (to M. J. Correia).
A preliminary account of this work has been published in abstract form (22).
Present address of T. Weng: Dept. of Physiology and Biophysics, The University of Texas Medical Branch, Galveston, Texas 77555-0641.
Address for reprint requests and other correspondence: K. J. Rennie, Rm. 7.102, Medical Research Bldg., UTMB, Galveston, TX 77555-1063 (E-mail: kjrennie{at}utmb.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 29 March 2000; accepted in final form 3 October 2000.
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