-
Pflugers Archiv : European Journal of... Oct 2016The cochlea of the mammalian inner ear contains an endolymph that exhibits an endocochlear potential (EP) of +80 mV with a [K(+)] of 150 mM. This unusual extracellular... (Review)
Review
The cochlea of the mammalian inner ear contains an endolymph that exhibits an endocochlear potential (EP) of +80 mV with a [K(+)] of 150 mM. This unusual extracellular solution is maintained by the cochlear lateral wall, a double-layered epithelial-like tissue. Acoustic stimuli allow endolymphatic K(+) to enter sensory hair cells and excite them. The positive EP accelerates this K(+) influx, thereby sensitizing hearing. K(+) exits from hair cells and circulates back to the lateral wall, which unidirectionally transports K(+) to the endolymph. In vivo electrophysiological assays demonstrated that the EP stems primarily from two K(+) diffusion potentials yielded by [K(+)] gradients between intracellular and extracellular compartments in the lateral wall. Such gradients seem to be controlled by ion channels and transporters expressed in particular membrane domains of the two layers. Analyses of human deafness genes and genetically modified mice suggested the contribution of these channels and transporters to EP and hearing. A computational model, which reconstitutes unidirectional K(+) transport by incorporating channels and transporters in the lateral wall and connects this transport to hair cell transcellular K(+) fluxes, simulates the circulation current flowing between the endolymph and the perilymph. In this model, modulation of the circulation current profile accounts for the processes leading to EP loss under pathological conditions. This article not only summarizes the unique physiological and molecular mechanisms underlying homeostasis of the EP and their pathological relevance but also describes the interplay between EP and circulation current.
Topics: Action Potentials; Animals; Cochlea; Deafness; Extracellular Fluid; Homeostasis; Humans; Potassium
PubMed: 27568193
DOI: 10.1007/s00424-016-1871-0 -
Frontiers in Cellular Neuroscience 2020The mammalian inner ear has two major parts, the cochlea is responsible for hearing and the vestibular organ is responsible for balance. The cochlea and vestibular...
The mammalian inner ear has two major parts, the cochlea is responsible for hearing and the vestibular organ is responsible for balance. The cochlea and vestibular organs are connected by a series of canals in the temporal bone and two distinct extracellular fluids, endolymph and perilymph, fill different compartments of the inner ear. Stereocilia of mechanosensitive hair cells in the cochlea and vestibular end organs are bathed in the endolymph, which contains high K ions and possesses a positive potential termed endolymphatic potential (ELP). Compartmentalization of the fluids provides an electrochemical gradient for hair cell mechanotransduction. In this study, we measured ELP from adult and neonatal C57BL/6J mice to determine how ELP varies and develops in the cochlear and vestibular endolymph. We measured ELP and vestibular microphonic response from saccules of neonatal mice to determine when vestibular function is mature. We show that ELP varies considerably in the cochlear and vestibular endolymph of adult mice, ranging from +95 mV in the basal turn to +87 mV in the apical turn of the cochlea, +9 mV in the saccule and utricle, and +3 mV in the semicircular canal. This suggests that ELP is indeed a local potential, despite the fact that endolymph composition is similar. We further show that vestibular ELP reaches adult-like magnitude around post-natal day 6, ~12 days earlier than maturation of cochlear ELP (i.e., endocochlear potential). Maturation of vestibular ELP coincides with the maturation of vestibular microphonic response recorded from the saccular macula, suggesting that maturation of vestibular function occurs much earlier than maturation of hearing in mice.
PubMed: 33364922
DOI: 10.3389/fncel.2020.584928 -
Hearing Research Jan 2008Epithelial cells of the inner ear coordinate their ion transport activity through a number of mechanisms. One important mechanism is the autocrine and paracrine... (Review)
Review
Epithelial cells of the inner ear coordinate their ion transport activity through a number of mechanisms. One important mechanism is the autocrine and paracrine signaling among neighboring cells in the ear via nucleotides, such as adenosine, ATP and UTP. This review summarizes observations on the release, detection and degradation of nucleotides by epithelial cells of the inner ear. Purinergic signaling is thought to be important for endolymph ion homeostasis and for protection from acoustic over-stimulation.
Topics: Acoustic Stimulation; Animals; Auditory Pathways; Ear, Inner; Endolymph; Epithelial Cells; Humans; Hydrolysis; Mechanotransduction, Cellular; Noise; Purine Nucleotides; Receptors, Purinergic; Receptors, Purinergic P1; Receptors, Purinergic P2; Signal Transduction
PubMed: 17980525
DOI: 10.1016/j.heares.2007.09.006 -
The Journal of Membrane Biology 2006Gap junctions play a critical role in hearing and mutations in connexin genes cause a high incidence of human deafness. Pathogenesis mainly occurs in the cochlea, where... (Review)
Review
Gap junctions play a critical role in hearing and mutations in connexin genes cause a high incidence of human deafness. Pathogenesis mainly occurs in the cochlea, where gap junctions form extensive networks between non-sensory cells that can be divided into two independent gap junction systems, the epithelial cell gap junction system and the connective tissue cell gap junction system. At least four different connexins have been reported to be present in the mammalian inner ear, and gap junctions are thought to provide a route for recycling potassium ions that pass through the sensory cells during the mechanosensory transduction process back to the endolymph. Here we review the cochlear gap junction networks and their hypothesized role in potassium ion recycling mechanism, pharmacological and physiological gating of cochlear connexins, animal models harboring connexin mutations and functional studies of mutant channels that cause human deafness. These studies elucidate gap junction functions in the cochlea and also provide insight for understanding the pathogenesis of this common hereditary deafness induced by connexin mutations.
Topics: Animals; Cochlea; Connexins; Disease Models, Animal; Gap Junctions; Hearing Loss; Homeostasis; Humans; Mice; Mutation
PubMed: 16773501
DOI: 10.1007/s00232-005-0832-x -
Frontiers in Molecular Neuroscience 2017The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of... (Review)
Review
The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells play the essential roles of providing physical and physiological support to sensory hair cells and of maintaining cochlear homeostasis. Appropriately enough, the gene most commonly mutated among subjects with hereditary hearing impairment (HI), , encodes the connexin-26 (Cx26) gap-junction channel protein that underlies both intercellular communication among supporting cells and homeostasis of the cochlear fluids, endolymph and perilymph. lies at the DFNB1 locus on 13q12. The specific kind of HI associated with this locus is caused by recessively-inherited mutations that inactivate the two alleles of the gene, either in homozygous or compound heterozygous states. We describe the many diverse classes of genetic alterations that result in DFNB1 HI, such as large deletions that either destroy the gene or remove a regulatory element essential for expression, point mutations that interfere with promoter function or splicing, and small insertions or deletions and nucleotide substitutions that target the coding sequence. We focus on how these alterations disrupt and Cx26 functions and on their different effects on cochlear development and physiology. We finally discuss the diversity of clinical features of DFNB1 HI as regards severity, age of onset, inner ear malformations and vestibular dysfunction, highlighting the areas where future research should be concentrated.
PubMed: 29311818
DOI: 10.3389/fnmol.2017.00428 -
Cellular Physiology and Biochemistry :... 2011Pendrin (SLC26A4, PDS) is an electroneutral anion exchanger transporting I(-), Cl(-), HCO(3)(-), OH(-), SCN(-) and formate. In the thyroid, pendrin is expressed at the... (Review)
Review
Pendrin (SLC26A4, PDS) is an electroneutral anion exchanger transporting I(-), Cl(-), HCO(3)(-), OH(-), SCN(-) and formate. In the thyroid, pendrin is expressed at the apical membrane of the follicular epithelium and may be involved in mediating apical iodide efflux into the follicle; in the inner ear, it plays a crucial role in the conditioning of the pH and ion composition of the endolymph; in the kidney, it may exert a role in pH homeostasis and regulation of blood pressure. Mutations of the pendrin gene can lead to syndromic and non-syndromic hearing loss with EVA (enlarged vestibular aqueduct). Functional tests of mutated pendrin allelic variants found in patients with Pendred syndrome or non-syndromic EVA (ns-EVA) revealed that the pathological phenotype is due to the reduction or loss of function of the ion transport activity. The diagnosis of Pendred syndrome and ns-EVA can be difficult because of the presence of phenocopies of Pendred syndrome and benign polymorphisms occurring in the general population. As a consequence, defining whether or not an allelic variant is pathogenic is crucial. Recently, we found that the two parameters used so far to assess the pathogenic potential of a mutation, i.e. low incidence in the control population, and substitution of evolutionary conserved amino acids, are not always reliable for predicting the functionality of pendrin allelic variants; actually, we identified mutations occurring with the same frequency in the cohort of hearing impaired patients and in the control group of normal hearing individuals. Moreover, we identified functional polymorphisms affecting highly conserved amino acids. As a general rule however, we observed a complete loss of function for all truncations and amino acid substitutions involving a proline. In this view, clinical and radiological studies should be combined with genetic and molecular studies for a definitive diagnosis. In performing genetic studies, the possibility that the mutation could affect regions other than the pendrin coding region, such as its promoter region and/or the coding regions of functionally related genes (FOXI1, KCNJ10), should be taken into account. The presence of benign polymorphisms in the population suggests that genetic studies should be corroborated by functional studies; in this context, the existence of hypo-functional variants and possible differences between the I(-)/Cl(-) and Cl(-)/HCO(3)(-) exchange activities should be carefully evaluated.
Topics: Alleles; Anions; Goiter, Nodular; Hearing Loss, Sensorineural; Humans; Ion Transport; Membrane Transport Proteins; Mutation; Polymorphism, Single Nucleotide; Sulfate Transporters; Vestibular Aqueduct
PubMed: 22116358
DOI: 10.1159/000335107 -
BMC Medical Genomics Jun 2023The primary pathological alterations of Pendred syndrome are endolymphatic pH acidification and luminal enlargement of the inner ear. However, the molecular...
BACKGROUND
The primary pathological alterations of Pendred syndrome are endolymphatic pH acidification and luminal enlargement of the inner ear. However, the molecular contributions of specific cell types remain poorly characterized. Therefore, we aimed to identify pH regulators in pendrin-expressing cells that may contribute to the homeostasis of endolymph pH and define the cellular pathogenic mechanisms that contribute to the dysregulation of cochlear endolymph pH in Slc26a4 mice.
METHODS
We used single-cell RNA sequencing to identify both Slc26a4-expressing cells and Kcnj10-expressing cells in wild-type (WT, Slc26a4) and Slc26a4 mice. Bioinformatic analysis of expression data confirmed marker genes defining the different cell types of the stria vascularis. In addition, specific findings were confirmed at the protein level by immunofluorescence.
RESULTS
We found that spindle cells, which express pendrin, contain extrinsic cellular components, a factor that enables cell-to-cell communication. In addition, the gene expression profile informed the pH of the spindle cells. Compared to WT, the transcriptional profiles in Slc26a4 mice showed downregulation of extracellular exosome-related genes in spindle cells. Immunofluorescence studies in spindle cells of Slc26a4 mice validated the increased expression of the exosome-related protein, annexin A1, and the clathrin-mediated endocytosis-related protein, adaptor protein 2.
CONCLUSION
Overall, cell isolation of stria vascularis from WT and Slc26a4 samples combined with cell type-specific transcriptomic analyses revealed pH-dependent alternations in spindle cells and intermediate cells, inspiring further studies into the dysfunctional role of stria vascularis cells in SLC26A4-related hearing loss.
Topics: Mice; Animals; Stria Vascularis; Anion Transport Proteins; Cochlea; Deafness; Sulfate Transporters; RNA
PubMed: 37322474
DOI: 10.1186/s12920-023-01549-0 -
Frontiers in Cellular Neuroscience 2021Inherited forms of deafness account for a sizable portion of hearing loss among children and adult populations. Many patients with sensorineural deficits have... (Review)
Review
Inherited forms of deafness account for a sizable portion of hearing loss among children and adult populations. Many patients with sensorineural deficits have pathological manifestations in the peripheral auditory system, the inner ear. Within the hearing organ, the cochlea, most of the genetic forms of hearing loss involve defects in sensory detection and to some extent, signaling to the brain the auditory cranial nerve. This review focuses on peripheral forms of hereditary hearing loss and how these impairments can be studied in diverse animal models or patient-derived cells with the ultimate goal of using the knowledge gained to understand the underlying biology and treat hearing loss.
PubMed: 34093131
DOI: 10.3389/fncel.2021.660812 -
Otolaryngologic Clinics of North America Oct 2010It is well established that endolymphatic hydrops plays a role in Ménière disease, even though the precise role is not fully understood and the presence of hydrops in... (Review)
Review
It is well established that endolymphatic hydrops plays a role in Ménière disease, even though the precise role is not fully understood and the presence of hydrops in the ear does not always result in symptoms of the disease. It nevertheless follows that a scientific understanding of how hydrops arises, how it affects the function of the ear, and how it can be manipulated or reversed could contribute to the development of effective treatments for the disease. Measurements in animal models in which endolymphatic hydrops has been induced have given numerous insights into the relationships between hydrops and other pathologic and electrophysiological changes, and how these changes influence the function of the ear. The prominent role of the endolymphatic sac in endolymph volume regulation, and the cascade of histopathological and electrophysiological changes that are associated with chronic endolymphatic hydrops, have now been established. An increasing number of models are now available that allow specific aspects of the interrelationships to be studied. The yclical nature of Ménière symptoms gives hope that treatments can be developed to maintain the ear in permanent state of remission, possibly by controlling endolymphatic hydrops, thereby avoiding the rogressive damage and secondary pathologic changes that may also contribute to the patient's symptoms.
Topics: Acute Disease; Aldosterone; Animals; Chronic Disease; Cyclic AMP; Disease Models, Animal; Endolymph; Endolymphatic Hydrops; Endolymphatic Sac; Hearing Loss; Humans; Intracranial Pressure; Ion Transport; Lipopolysaccharides; Magnetic Resonance Imaging; Noise; Vasopressins
PubMed: 20713237
DOI: 10.1016/j.otc.2010.05.007 -
Annals of the New York Academy of... Nov 1999The most common ototoxic compounds in clinical practice are aminoglycoside antibiotics, cisplatin, and loop diuretics (ethacrynic acid and furosemide). These agents also... (Review)
Review
The most common ototoxic compounds in clinical practice are aminoglycoside antibiotics, cisplatin, and loop diuretics (ethacrynic acid and furosemide). These agents also have substantial renal effects in the form of nephrotoxicity or diuresis. The understanding of these renal effects may provide insight into ototoxic mechanisms. For aminoglycosides, the renal proximal tubule cell is susceptible due to high concentration achieved and slow clearance with direct effects on phosphoinositide binding and mitochondrial bioenergetics. Pathogenesis appears to involve iron-induced free-radical formation, since iron chelators prevent nephrotoxicity. Analogous effects of aminoglycosides on the inner and outer hair cells have been observed. Cisplatin is also highly concentrated in the proximal tubule cell. Less is known about the direct toxic effects of this agent on renal cells. Insights into mechanisms or renal tubule cells could be directly relevant to the inner ear. The loop diuretics are direct inhibitors of the Na(+)-K(+)-2Cl- cotransport system, which also exists in the marginal and dark cells of the stria vascularis, which are responsible for endolymph secretion. The ototoxicity of these agents may be indirect, due to changes in ionic composition and fluid volume within the endolymph.
Topics: Aminoglycosides; Anti-Bacterial Agents; Antineoplastic Agents; Cisplatin; Diuretics; Ear, Inner; Humans; Kidney
PubMed: 10842580
DOI: 10.1111/j.1749-6632.1999.tb00278.x