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At least 19 recordsLinked to original sources
PubMed2004

A "synaptoplasmic cistern" mediates rapid inhibition of cochlear hair cells.

Cochlear hair cells are inhibited by cholinergic efferent neurons. The acetylcholine (ACh) receptor of the hair cell is a ligand-gated cation channel through which calcium enters to activate potassium channels and hyperpolarize the cell. It has been proposed that calcium-induced calcium release (CICR) from a near-membrane postsynaptic store supplements this process. Here, we demonstrate expression of type I ryanodine receptors in outer hair cells in the apical turn of the rat cochlea. Consistent with this finding, ryanodine and other store-active compounds alter the amplitude of transient currents produced by synaptic release of ACh, as well as the response of the hair cell to exogenous ACh. Like the sarcoplasmic reticulum of muscle, the "synaptoplasmic" cistern of the hair cell efficiently couples synaptic input to CICR.

Acetylcholine↗
PubMed1999

A molecular mechanism for electrical tuning of cochlear hair cells.

Cochlear frequency selectivity in lower vertebrates arises in part from electrical tuning intrinsic to the sensory hair cells. The resonant frequency is determined largely by the gating kinetics of calcium-activated potassium (BK) channels encoded by the slo gene. Alternative splicing of slo from chick cochlea generated kinetically distinct BK channels. Combination with accessory beta subunits slowed the gating kinetics of alpha splice variants but preserved relative differences between them. In situ hybridization showed that the beta subunit is preferentially expressed by low-frequency (apical) hair cells in the avian cochlea. Interaction of beta with alpha splice variants could provide the kinetic range needed for electrical tuning of cochlear hair cells.

Alternative Splicing↗
PubMed2006

The sensory and motor roles of auditory hair cells.

Cochlear hair cells respond with phenomenal speed and sensitivity to sound vibrations that cause submicron deflections of their hair bundle. Outer hair cells are not only detectors, but also generate force to augment auditory sensitivity and frequency selectivity. Two mechanisms of force production have been proposed: contractions of the cell body or active motion of the hair bundle. Here, we describe recently identified proteins involved in the sensory and motor functions of auditory hair cells and present evidence for each force generator. Both motor mechanisms are probably needed to provide the high sensitivity and frequency discrimination of the mammalian cochlea.

Animals↗
PubMed1988

Characteristics of the membrane of the stereocilia and cell apex in cochlear hair cells.

Freeze-fracture has been used to examine the membrane of the cell apex and of the stereocilia in cochlear hair cells. The apical (non-stereociliary) membrane of inner hair cells (IHCs) exhibited a lower density of intramembrane particles (IMP) than that of the outer hair cells (OHCs) but in both cell types the apical membrane responded to the effects of filipin. The distribution of IMP and of filipin-induced membrane deformations was uniform over the apical membranes in both IHC and OHC, thus, providing no evidence for local membrane differentiation on the non-stereociliary part of the hair cell apex. The stereociliary membranes of IHC and of OHC differed not only in the density of IMP, but also in their responses to filipin and to tomatin. IHC stereocilia responded intensely to both agents. OHC stereocilia showed a significantly lower density of filipin-induced lesions and appeared almost unaffected by tomatin. This suggests that the OHC stereocilial membrane may be structurally specialized. The membrane at the apical end of stereocilia appeared to be differentiated from the membrane of the stereociliary shaft. The tip region was free of the usual IMP and showed no filipin-induced lesions. The differentiation at the apical end was also apparent in samples which have been rapidly frozen without prior chemical fixation or cryoprotection, showing that the particle-free area was not an artefact induced by glutaraldehyde fixation. Close examination of the membrane at the apical-most tip of the stereocilium revealed the presence of a small number of large particles of 10.5-11.0 nm diameter. The occurrence of membrane differentiation localized to the tip of the stereocilium may be consistent with the suggestion that transduction channels in hair cells are situated at this point.

Animals↗
PubMed2001

A modified adenovirus can transfect cochlear hair cells in vivo without compromising cochlear function.

The loss of cochlear hair cells, or the loss of their capacity to transduce acoustic signals, is believed to be the underlying mechanism in many forms of hearing loss. To develop viral vectors that allow for the introduction of genes directly into the cochleae of adult animals, replication-deficient (E1(-), E3(-)) and replication-defective (E1(-), E3(-), pol(-)) adenovirus vectors were used to transduce the bacterial beta-galactosidase gene into the hair cells of the guinea pig cochlea in vivo. Distortion product otoacoustic emissions, which monitor the functional status of outer hair cells, were measured throughout the viral infection periods to identify hair cell ototoxicity. The results demonstrated that the use of the (E1(-), E3(-)) adenovirus vectors containing CMV-driven LacZ, compromised cochlear function when gradually introduced into scala tympani via an osmotic pump. However, when (E1(-), E3(-), pol(-)) adenoviral vectors containing CMV-driven LacZ were used to transduce cochlear hair cells, there was no loss of cochlear function over the frequency regions tested, and beta-galactosidase (beta-gal) was detected in over 80% of all hair cells. Development of a viral vector that infects cochlear hair cells without virus-induced ototoxic effects is crucial for gene replacement strategies to treat certain forms of inherited deafness and for otoprotective strategies to prevent hair cell losses to treat progressive hearing disorders. Moreover, in vivo (E1(-), E3(-), pol(-)) adenovirus mediated gene-transfer techniques applied to adult guinea pig cochleae may be useful in testing several hypotheses concerning what roles specific genes play in normal cochlear function.

Adenoviridae↗
PubMed2001

The voltage-sensitive motor protein and the Ca2+-sensitive cytoskeleton in developing rat cochlear outer hair cells.

Cochlear outer hair cells (OHCs) possess a unique fast voltage-driven motility associated with a voltage-sensitive motor protein embedded in the basolateral membrane. This mechanism is believed to underlie the cochlear amplification in mammals. OHCs also have a Ca2+/calmodulin-dependent mechanical pathway which involves a submembranous circumferential cytoskeleton. The purpose of this study was to compare the functional appearance of the voltage-sensitive motor proteins with that involving the Ca2+-sensitive cytoskeleton during postnatal development of rat OHCs. We demonstrate that whole-cell electromotility and Ca2+-voked mechanical responses, by ionomycin, develop concomitantly after postnatal day 5 (P5). These two mechanical properties also develop simultaneously in OHCs isolated from two-week-old cultures of P0-P1 organs of Corti. This excludes the participation of neural innervation in the postnatal maturation of the OHCs' motile properties. In addition, we show that the expression of the membranous voltage-sensitive motor protein precedes, by several days, the appearance of whole-cell electromotility. The concomitant development of whole-cell electromotility and Ca2+-sensitive motility, both in vivo and in vitro, underlines the cytoskeleton as an important factor in the functional organization of the voltage-sensitive motor proteins within the plasma membrane.

Aging↗
PubMed1989

Aminoglycoside antibiotics impair calcium entry but not viability and motility in isolated cochlear outer hair cells.

Cochlear outer hair cells have been well established as primary targets of the ototoxic actions of aminoglycoside antibiotics. These cells, isolated from the guinea pig cochlea and maintained in short-term culture, were used as a model for evaluating the acute effects of gentamicin on cell viability, depolarization-induced transmembrane calcium flux, and depolarization-induced motile responses. On the basis of morphology and fluorochromasia, the presence of extracellular gentamicin as high as 5 mM did not affect the viability of the cells for up to 6 hr, the longest time tested. Viable cells showed binding of fluorescently tagged gentamicin to their base but excluded the drug from their cytoplasm. In response to [K+]-depolarization, intracellular calcium levels (monitored with the fluorescent calcium-sensitive dye fluo-3) increased from a resting value of 218 +/- 102 nM to 2,018 +/- 1,077 nM concomitant with a cell shortening of 0.7% +/- 1.3%. The depolarization-induced calcium increase was apparently caused by calcium entry into the cell as it was inhibited by the calcium-channel blocker methoxyverapamil and prevented in the absence of extracellular calcium. Both gentamicin and neomycin blocked the [K+]-induced calcium increase at an IC50 of 50 microM. Despite the inhibition of calcium entry the ability of the outer hair cells to shorten under [K+]-depolarization was not impaired; in fact, cell shortening was even more pronounced in the absence of calcium influx (2.6% +/- 1.4%). This argues effectively against the existence of a calcium-dependent actomyosin-mediated component in [K+]-induced shape changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Evidence that phosphoinositides mediate motility in cochlear outer hair cells.

Cochlear outer hair cells are postulated to modulate auditory transduction by their mechanical properties which presumably are controlled by efferent neurons and regulated by the levels of intracellular calcium. In a number of biological systems these calcium levels are controlled by inositol trisphosphate (InsP3), the second messenger of the phosphoinositide cascade. We have investigated whether the phosphoinositides function in the signal transfer in mammalian auditory sensory cells. Live isolated outer hair cells synthesize the lipids of the phosphoinositide cycle, phosphatidic acid (Ptd), phosphatidylinositol (PtdIns), phosphatidylinositol 4-phosphate (PtdInsP) and phosphatidylinositol 4,5-bisphosphate (PtdInsP2). After one hour of incubation with [32P]orthophosphate, Ptd constituted 21 +/- 7% of labeled lipids, PtdIns 19 +/- 5%, PtdInsP 28 +/- 7% and PtdInsP2 33 +/- 7%. Contractions were elicited in isolated cells after their membrane was permeabilized with Triton X-100. Addition of calcium and ATP resulted in contractions (average, 7.2% of initial cell length) in 81% of the cells studied; the omission of ATP or calcium (i.e. the presence of the calcium-chelator EGTA) reduced the incidence of contractions to 0% and 17%, respectively. In the absence of calcium, the putative second messenger, InsP3, caused contractions in 63% of the observed cells while the physiologically inactive agents inositol and inositol bisphosphate failed to elicit responses. The results are compatible with the suggestion that InsP3 mediates contractility in outer hair cells.

Animals↗
PubMed2001

Tetraethylammonium ions block the nicotinic cholinergic receptors of cochlear outer hair cells.

Cochlear outer hair cells (OHCs) express nicotinic acetylcholine receptors (nAChRs) whose calcium permeability allow the activation of co-localized Ca(2+)-sensitive K+ channels (SK-type). The large organic cation tetraethylammonium (TEA) is known to block at millimolar concentration voltage-gated and Ca(2+)-activated K+ currents in OHCs. In the present study, we show that extracellular TEA blocked much more efficiently, at micromolar concentrations, ACh-evoked K+ currents in isolated guinea pig OHCs. The dose-inhibition curve indicated an IC(50) of 60 microM, a value two orders of magnitude lower than the one reported on SK or BK channels. The site of the blocking action was on the extracellular side of the plasma membrane since 10 mM intracellular TEA did not prevent or change the characteristics of the ACh-evoked K+ current. The block of this K+ current in OHCs was mainly explained by a direct action of TEA at the nAChRs. Indeed, we demonstrated that extracellular TEA inhibited directly the ionotropic cation current flowing through the nAChRs (IC(50)=30 microM). This study demonstrated for the first time that extracellular TEA is an effective blocker of the OHCs' nAChRs.

Acetylcholine↗
PubMed2005

Effectiveness, active energy produced by molecular motors, and nonlinear capacitance of the cochlear outer hair cell.

Cochlear outer hair cells are crucial for active hearing. These cells have a unique form of motility, named electromotility, whose main features are the cell's length changes, active force production, and nonlinear capacitance. The molecular motor, prestin, that drives outer hair cell electromotility has recently been identified. We reveal relationships between the active energy produced by the outer hair cell molecular motors, motor effectiveness, and the capacitive properties of the cell membrane. We quantitatively characterize these relationships by introducing three characteristics: effective capacitance, zero-strain capacitance, and zero-resultant capacitance. We show that zero-strain capacitance is smaller than zero-resultant capacitance, and that the effective capacitance is between the two. It was also found that the differences between the introduced capacitive characteristics can be expressed in terms of the active energy produced by the cell's molecular motors. The effectiveness of the cell and its molecular motors is introduced as the ratio of the motors'active energy to the energy of the externally applied electric field. It is shown that the effectiveness is proportional to the difference between zero-strain and zero-resultant capacitance. We analyze the cell and motor's effectiveness within a broad range of cellular parameters and estimate it to be within a range of 12%-30%.

Animals↗
PubMed2003

CaV1.3 channels are essential for development and presynaptic activity of cochlear inner hair cells.

Cochlear inner hair cells (IHCs) release neurotransmitter onto afferent auditory nerve fibers in response to sound stimulation. During early development, afferent synaptic transmission is triggered by spontaneous Ca2+ spikes of IHCs, which are under efferent cholinergic control. Around the onset of hearing, large-conductance Ca2+-activated K+ channels are acquired, and Ca2+ spikes as well as the cholinergic innervation are lost. Here, we performed patch-clamp measurements in IHCs of mice lacking the CaV1.3 channel (CaV1.3-/-) to investigate the role of this prevailing voltage-gated Ca2+ channel in IHC development and synaptic function. The small Ca2+ current remaining in IHCs from 3-week-old CaV1.3-/- mice was mainly mediated by L-type Ca2+ channels, because it was sensitive to dihydropyridines but resistant to inhibitors of non-L-type Ca2+ channels such as omega-conotoxins GVIA and MVIIC and SNX-482. Depolarization induced only marginal exocytosis in CaV1.3-/- IHC, which was solely mediated by L-type Ca2+ channels, whereas robust exocytic responses were elicited by photolysis of caged Ca2+. Secretion triggered by short depolarizations was reduced proportionally to the Ca2+ current, suggesting that the coupling of the remaining channels to exocytosis was unchanged. CaV1.3-/- IHCs lacked the Ca2+ action potentials and displayed a complex developmental failure. Most strikingly, we observed a continued presence of efferent cholinergic synaptic transmission and a lack of functional large-conductance Ca2+-activated K+ channels up to 4 weeks after birth. We conclude that CaV1.3 channels are essential for normal hair cell development and synaptic transmission.

Aging↗
PubMed1984

Preferential glutamine uptake by cochlear hair cells: implications for the afferent cochlear transmitter.

The cochlear uptake of amino acids which are putative neurotransmitters, or closely-related compounds, was examined autoradiographically in the gerbil. Hair cells showed no preferential uptake of most compounds tested. However, preferential accumulation of glutamine by cochlear hair cells was striking. Vestibular hair cells showed no affinity for this amino acid. Glutamine uptake by cochlear hair cells may play an important role in afferent synaptic transmission, by providing transmitter precursor and/or by clearing the synaptic cleft.

Afferent Pathways↗
PubMed1994

Position-dependent expression of potassium currents by chick cochlear hair cells.

1. Potassium currents in chick cochlear hair cells were studied using whole-cell voltage clamp techniques. Cells were isolated from 200 microns-long segments of the apical half of the cochlea. In each segment, expression of potassium currents by cells positioned across the width ('inner-outer' hair cell axis) of the cochlea was examined. 2. A rapidly inactivating potassium current (IA) was found in some hair cells. At a membrane potential of -24 mV, IA activated to peak values within 7 +/- 1 ms and inactivated within 73 +/- 16 ms. The activation 'threshold' was around -50 mV and hyperpolarization more negative than -56 +/- 5 mV was required before significant removal of inactivation occurred (V 1/2 (half-inactivation potential) = -74 +/- 5 mV). The resting potential of cells with IA was -46 mV +/- 11 mV. This current was blocked by 4-aminopyridine with a Kd of 0.45 mM. 3. Cells that were isolated from the most apical tip of the cochlea expressed no IA. In areas more basal than 200 microns from the apex, the magnitude of IA correlated with cell morphology. In each area, the tallest hair cells (cells with the smallest ratio of apical surface diameter to length) had none of this current. Of the cells with IA, the shorter cells (larger ratio of apical surface diameter to length) had more of this current. 4. The magnitude of IA in a cell was dependent upon cross-cochlear position, and the relationship between IA and cell morphology was most probably a reflection of a differential distribution of cell shape across the cochlea. The tallest hair cells, occupying roughly the first 40% of the distance from the neural side of the basilar papilla, had no IA. Of the remaining cells, those nearer to the abneural edge expressed more IA, such that iso-magnitude lines ran approximately parallel to the long axis of the cochlea. 5. A delayed rectifier current (IK) and an inward rectifier current (IIR) were also differentially distributed among hair cells across the cochlea; however, their distribution differed from that of IA. IK and IIR were preferentially expressed by the taller hair cells, which were positioned nearer to the neural side of the cochlea. Ca(2+)-activated potassium current (IK(Ca)) did not vary systematically between cells of different shape or cross-cochlear position, and IK(Ca) could often be found in cells with IA.

4-Aminopyridine↗
PubMed1999

A missense mutation in myosin VIIA prevents aminoglycoside accumulation in early postnatal cochlear hair cells.

Myosin VIIA is expressed by sensory hair cells in the inner ear and proximal tubule cells in the kidney, the two primary targets of aminoglycoside antibiotics. Using cochlear cultures prepared from early postnatal Myo7a6J mice with a missense mutation in the head region of the myosin VIIA molecule we show that this myosin is required for aminoglycoside accumulation in cochlear hair cells. Hair cells in homozygous mutant Myo7a6J cochlear cultures have disorganized hair bundles, but are otherwise morphologically normal and transduce. However, and in contrast to hair cells from heterozygous Myo7a6J cultures, the homozygous Myo7a6J hair cells do not accumulate [3H]gentamicin and do not exhibit an ototoxic response on exposure to aminoglycoside. Possible roles for myosin VIIA in the process of aminoglycoside accumulation are discussed.

Animals↗
PubMed1994

Single channel recordings of calcium currents in chick cochlear hair cells.

Single Ca2+ channel currents were recorded from chick cochlear hair cells by using cell-attached patches. The elementary current was about -2 pA at 70 mV positive to the resting potential (R.P.+ 70 mV); the slope conductance over a 40 mV voltage range was 24 pS. The open time histogram was reasonably well expressed by a single exponential function, while the closed time histogram was expressed by a sum of two exponential functions. The Ca2+ channel was activated around R.P.+ 60 mV and the average ensemble current did not decay during 130 ms depolarization, suggesting that the Ca2+ channel in chick cochlear hair cells is the L-type. The Ca2+ channel has three modes of gating behaviour, expressed as current records with brief openings (mode I), no openings (mode 0), or long-lasting openings and very brief closings (mode 2).

Animals↗
PubMed1986

Alcian blue staining of cochlear hair cell stereocilia and other cochlear tissues.

Using whole-mount surface preparations of the chinchilla organ of Corti, the anionic characteristics of cochlear tissues was investigated with the polycationic dye Alcian Blue. Our primary goal was to specifically stain the hair cell stereocilia for the purpose of producing cytocochleograms. To specifically stain hair cell stereocilia we investigated the effects of different fixatives and the 'critical electrolyte concentration' [Scott and Dorling (1965) Histochemie 5, 221-233] of MgCl2 on staining specificity. The stereocilia and the tectorial membrane were the most intensely stained cochlear structures and presumably have a strong negative charge. The most important factor in producing specific staining was fixation in osmium tetroxide rather than the addition of an electrolyte to the Alcian Blue staining solution. The use of Alcian Blue produced intense staining of hair cell stereocilia against an unstained background using standard, brightfield light microscopy.

Alcian Blue↗
PubMed2002

Avian brainstem neurogenesis is stimulated during cochlear hair cell regeneration.

Unlike mammals, adult avians are able to regenerate cochlear sensory hair cells following injury. Brainstem auditory neurons in chicken nucleus magnocellularis (NM), which receive their sole excitatory afferent input from the cochlea, were examined for evidence of mitosis during ototoxin-induced loss and regeneration of cochlear hair cells. Using tritiated thymidine as a mitotic marker in tissue processed for autoradiography and counterstained with thionin, labeled NM neurons and glia were counted from chickens killed 16 days after gentamicin or saline injections. Newly generated NM neurons were observed during cochlear hair cell regeneration. More labeled neurons were observed in the experimental chickens, but a few were also seen in the control chickens. We predicted labeled NM neurons would be found solely in the rostral high frequency region, given the gentamicin-induced high frequency cochlear hair cell loss and regeneration. However, the labeled NM neurons were located throughout the tonotopic axis of the nucleus. The total number of labeled neurons was lower than predicted. Many labeled NM glia were observed in experimental and control chickens. Labeled cells were also observed throughout the chicken brainstem and cerebellum in both experimental and control chickens, indicating great potential for CNS plasticity. Results in NM indicate the avian auditory system is capable of regenerating brainstem auditory neurons in addition to the previously well-established capability of regenerating cochlear hair cells in response to ototoxic injury. Recovery of both central and peripheral auditory components will be necessary to restore hearing damaged by noise or ototoxic drugs.

Afferent Pathways↗