Review
Ion flow in stria vascularis and the production and regulation of cochlear endolymph and the endolymphatic potential

https://doi.org/10.1016/j.heares.2011.01.010Get rights and content

Abstract

This paper reviews some of what is known about ion transport through the cells of the mammalian stria vascularis, and discusses how the endolymph and endocochlear potential in scala media are produced by the stria’s main cell types. It discusses the role of each cells’ ion transport proteins from an engineering perspective, and the advantages and disadvantages in using the different transport proteins in the different cells to perform their different roles. To aid this discussion, the use of spreadsheet analysis in the modelling of ion transport in single cells and homogenous epithelia is outlined, including the current-voltage (IV) characteristics of the three main categories of transport proteins (pores, ports and pumps), and the constraint equations that apply under various conditions (the voltage or ionic steady states in the open- and closed-circuit conditions). Also discussed are the circulation of K+ within the cochlea, and the chloride, salt and water balance of scala media and stria vascularis, and what transport processes may be required to maintain such a balance.

Highlights

► Ion transport proteins and cell topology in stria vacularis are summarised. ► Regulation of endocochlear potential and endolymph composition are discussed. ► Spreadsheet analysis of epithelial transport is described.

Introduction

This paper and an accompanying one (Patuzzi, in press) discuss from an engineering perspective how the cochlea’s ion transport proteins (Fig. 1) combine to produce an acoustic sensor that is sensitive, stable and self-starting at birth. The two papers are not about the detailed molecular biology of each ion transporter (the channels or pores, the passive co-transporters or ports/symports/antiports, and the active pumps), because there are already excellent reviews covering their gene sequences and subunits, the mutations leading to deafness, their localization within the cochlea, their development, and their behaviour (Couloigner et al., 2006; Herbert et al., 2005, Hibino and Kurachi, 2006; Housley et al., 2006; Jentsch et al., 2002, Lang et al., 2007, Marcus and Wangemann, 2009, Nin et al., 2008, Petit et al., 2001, Petit, 2006, Wangemann and Schacht, 1996, Wangemann, 2006, Wangemann, 2008). While molecular biology in hearing research has provided enormous detail about the cochlea’s protein transporters, there is not yet an overview of how they interact to produce cochlear regulation, and that is the focus of the present two papers. This paper focuses on stria vascularis and the generation of endolymph and the endocochlear potential (EP), including the mathematical modelling of ion transport in strial cells, while the other focuses on hair cells and their autoregulation. Separating the function of hair cells from that of stria vascularis is difficult, because they are tied together in a ‘push-pull’ or ‘pump-leak’ balance that determines not only the EP and endolymph composition, but ultimately the sensitivity and stability of hair cells and hearing over a life time. The composition of endolymph and the value of the EP are determined by a balance between the active electrogenic extrusion of K+ into scala media by stria vascularis, and by the passive ‘drainage’ of K+ from scala media, largely through the organ of Corti and its mechanically-sensitive hair cells (Fig. 1). The EP is important in providing about half of the driving potential for the hair cell receptor current, while the composition of endolymph is important in the cochlea’s salt and water balance, which in turn determines the static pressure bias on the hair cells, and therefore the saturation of their receptor current and hearing threshold. This paper discusses the evolutionary advantage of endolymph and the high EP in mammals, summarizes some of strial structure and function, and then touches on salt and water balance in the cochlea before finally discussing the spreadsheet analysis of ion flow through asymmetric cells, like those of the organ of Corti and stria vascularis. The accompanying paper addresses ion transport in the mammalian hair cells, how fluctuations in EP and cochlear fluid pressure alter cochlear sensitivity, and how the hair cells’ ion transporters might buffer hearing sensitivity against changes in EP and endolymph, ultimately suggesting experiments that might answer an important outstanding question in cochlear function: which electromotile process enhances vibration of the organ of Corti.

Section snippets

Why produce endolymph and a high (+95 mV) EP?

In most mechano-sensory cells there is a large stimulus, so that sensitivity and signal-to-noise ratio are not a concern. In such cases the receptor current is carried by Na+ ions which enter passively but must be actively extruded to avoid salt accumulation and cell swelling, which is clearly a problem in mechano-sensitive cells. Progressively during the evolution of mechano-sensory systems, the use of Na+ as a receptor current would presumably have become a problem, partly due to noise from

Strial structure and development

While the production of endolymph and the high +95 mV EP have distinct advantages, they come at a high cost: stria vascularis has one of the highest metabolic rates per gram of any body tissue (Johnstone, 1971), and must start in utero, initially with all cells surrounded by a Na+-rich fluid. This places such severe constraints on the ‘design’ of the stria’s pumping cells that no single cell layer could perform these tasks. Evolution seems to have solved this problem with an extraordinarily

Evidence for strial transport mechanisms

There is a long list of experimental clues to the transport mechanisms in stria vascularis: (i) there is a net outward K+ current from MCs, as indicated by the high EP and K+ rich endolymph (von Békésy, 1960, Tasaki and Spyropoulos, 1959); (ii) hypoxia (Bosher, 1979; Kuijipers and Bonting, 1970) and cyanide (Konishi and Kelsey, 1973) reduce EP, due to a drop in metabolism and strial current (Tasaki and Spyropolous, 1959); (iii) prolonged hypoxia also produces a drop in endolymphatic K+ and a

K+ circulation in the cochlea

It has been suggested that once K+ passes through the hair cells, it (passively) recycles through the cells of the basilar membrane and spiral ligament via K+ channels or KCl co-transporters (the KCC symports), to be used again by the stria and extruded into scala media. While consistent with (but not implied by) the early evidence from K+ tracer experiments showing that the extruded K+ came from the spiral ligament and not from the strial capillaries (Salt et al., 1987, Shindo et al., 1992),

Strial models and single-cell analysis

An understanding of ion transport in stria vascularis requires a consistent model of ion transport, using the known properties of known transport proteins. Unfortunately, most conceptual models of the stria (there have been very few mathematical ones) have been less than stringent. While Sellick and Johnstone (1975) were ahead of their time in considering the electrical and chemical gradients for K+ in MCs, they did not consider the source of Na+ or Cl into these cells, and the K+ pump they

Mathematical aspects of cell analysis

Ultimately, a full understanding of the concerted action of the transport proteins in any cell or complex epithelium requires a full mathematical modelling of the solute and water transport through the cell’s membranes. This is true whether we are interested in simply the resting electrical potentials within the cells, or in the details of the complete ion/solute flow through the cells and extracellular compartments. While this analysis has been done with dedicated software for specific cells,

Acknowledgments

Early modelling and initial work on stria vascularis were done in collaboration in vivo with Dr. Simon Marcon, and in vitro with Dr. Susmita Thomson. The spreadsheet modelling described was developed by the author over many years for undergraduate students at The University of Western Australia. Some of this paper is based on a talk given at ARO in 2002, at a symposium honouring my long-time research colleague, the late Dr. Graeme Yates.

References (148)

  • D. Marcus et al.

    Potassium secretion by vestibular dark cell epithelium demonstrated by vibrating probe

    Biophysical J.

    (1994)
  • D. Marcus et al.

    Transepithelial voltage and resistance of vestibular dark cell epithelium from the gerbil ampulla

    Hear. Res.

    (1994)
  • D. Marcus et al.

    Sidedness of action of loop diuretics and ouabain on nonsensory cells of utricle: a micro-Ussing chamber for inner ear tissues

    Hear. Res.

    (1987)
  • D. Marcus et al.

    Changes in cation contents of stria vascuiaris with ouabain and potassium-free perfusion

    Hear. Res.

    (1981)
  • D. Marcus et al.

    Effects of barium and ion substitution in artificial blood on endocochlear potential

    Hear. Res.

    (1985)
  • D. Marcus et al.

    Response of cochlear potentials to presumed alterations of ionic conductance: endolymphatic perfusion of barium, valinomycin and nystatin

    Hear. Res.

    (1983)
  • D.C. Marcus et al.

    Protein kinase C mediates P2U purinergic receptor inhibition of K+ channel in apical membrane of strial marginal cells

    Hear. Res.

    (1998)
  • D.C. Marcus et al.

    K+ and Na+ absorption by outer sulcus epithelial cells

    Hear. Res.

    (1999)
  • I. Melichar et al.

    Electrophysiologicai measurements of the stria vascularis potentials in vivo

    Hear. Res.

    (1987)
  • H. Mori et al.

    Permeability to chloride ions of the cochlear partition in normal guinea pigs

    Hear. Res.

    (1985)
  • A.P. Nenov et al.

    Outward rectifying potassium currents are the dominant voltage activated currents present in Deiters’ cell

    Hear. Res.

    (1998)
  • M.-T. Nicolas et al.

    KCNQ1/KCNE1 potassium channels in mammalian vestibular dark cells

    Hear. Res.

    (2001)
  • F.F. Offner et al.

    Positive endocochlear potential: mechanism of production by marginal cells of stria vascularis

    Hear. Res.

    (1987)
  • A.J. Pace et al.

    Ultrastructure of the inner ear of NKCC1-deficient mice

    Hear. Res.

    (2001)
  • C. Petit

    From deafness genes to hearing mechanisms: harmony and counterpoint

    Trends Mol. Med.

    (2006)
  • D. Pike et al.

    The time course of the strial changes produced by intravenous furosemide

    Hear. Res.

    (1980)
  • M. Ando et al.

    Immunological identification of an inward rectifier K+ channel Kir4.1 in the intermediate cell (melanocyte) of the cochlear stria vascularis of gerbils and rats

    Cell Tissue Res.

    (1999)
  • D. Bagger-Sjoback et al.

    Freeze-fracturing of the human stria vascularis

    Acta Otolaryngol. (Stockh)

    (1987)
  • M.P. Blaustein et al.

    Sodium/Calcium exchange: its physiological implications

    Physiol. Rev.

    (1999)
  • T. Boettger et al.

    Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold

    EMBO J.

    (2003)
  • S.K. Bosher

    The nature of the negative endocochlear potentials produce by anoxia and ethacrynic acid in the rat and the guinea pig

    J. Physiol.

    (1979)
  • S.K. Bosher

    The nature of the ototoxic actions of ethacrynic acid upon the mammalian endolymph system: 1. Functional Aspects

    Acta Otolaryngol.

    (1980)
  • S.K. Bosher

    The nature of the ototoxic actions of ethacrynic acid upon the mammalian endolymph system: 2.Structural-functional correlates in the stria vascularis

    Acta Otolaryngol.

    (1980)
  • S.K. Bosher

    The nature of the ototoxic actions of ethacrynic acid upon mammalian endolymph system

    Arch. Otorhinolaryngol.

    (1980)
  • A.M. Butt et al.

    Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions

    J. Cell. Mol. Med.

    (2006)
  • J. Cable et al.

    Effects of mutations at the W locus (c-kit) on inner ear pigmentation and function in the mouse

    Pigment Cell Res.

    (1994)
  • M. Carmosino et al.

    Exon loss accounts for differential sorting of Na-K-Cl cotransporters in polarized epithelial cells

    Mol. Biol. Cell

    (2008)
  • J.B. Chapmann

    Thermodynamics and kinetics of electrogenic pumps

  • J.T.Y. Chou et al.

    Resting membrane potential of the strial cells of the guinea pig

    Experientia

    (1975)
  • M. Cohen-Salmon

    Connexins responsible for hereditary deafness: the tale unfolds

  • P. De Weer

    Electrogenic pumps: Theoretical and practical considerations

  • M.J. Dixon et al.

    Mutation of the Na-K-CI co-transporter gene SIc12a2 results in deafness in mice

    Hum. Mol. Genet.

    (1999)
  • D. Dulon

    Ca2+ signaling in Deiters cells of the guinea-pig cochlea: active process in supporting cells?

  • A. Duvall et al.

    Mannitol-induced stria vascularis edema

    Arch. Otolaryngol.

    (1981)
  • D.L. Eng et al.

    Development of 4-AP and TEA sensitivities in mammalian myelinated nerve fibers

    J. Neurophys

    (1988)
  • R. Estevez et al.

    Barttin is a Cl-channel beta-subunit crucial for renal Cl reabsorption and inner ear K+ secretion

    Nature

    (2001)
  • C. Fahlke

    Ion permeation and selectivity in ClC-type chloride channels

    Am. J. Physiol.

    (2001)
  • A. Forge et al.

    Assessment of ultrastructure in isolated cochlear hair cells using a procedure for rapid freezing before freeze-fracture and deep-etching

    J. Neurocytol.

    (1991)
  • P.J. Garrahan et al.

    A kinetic study of the Na pump in red cells: its relevance to the mechanism of active transport. Ann N

    Y. Acad. Sci.

    (1974)
  • H. Garty et al.

    Characteristics and regulatory mechanisms of the amiloride-blockable Na+ channel

    Physiol. Revs

    (1988)
  • Cited by (70)

    • The role of the stria vascularis in neglected otologic disease

      2023, Hearing Research
      Citation Excerpt :

      Mutations in genes encoding ion channels in these cell types are known to cause deafness and EP dysfunction. Previous studies have extensively delineated the critical functions that specific ionic channels accomplish, including their role in EP generation and in regulating ion homeostasis (Chen, J. and Zhao, H.B., 2014; Patuzzi, 2011; Zdebik et al., 2009). SV cell types maintain the EP through the active transport of ions and tightly regulate the flow of molecules between the bloodstream and the endolymph, likely contributing to the blood-labyrinthine barrier (BLB).

    • Identifying targets to prevent aminoglycoside ototoxicity

      2022, Molecular and Cellular Neuroscience
    • Hearing loss caused by CMV infection is correlated with reduced endocochlear potentials caused by strial damage in murine models

      2022, Hearing Research
      Citation Excerpt :

      This mechanism was well described and modeled in Davis's “battery theory” (Davis 1958; 1965). The EP is maintained by a high concentration of potassium ions pumped into scala media by metabolically active ion exchange pumps closely associated with stria vascularis (e.g. Patuzzi 2011; Salt et al. 1987). The strial capillary network supplies oxygen for these high demand metabolic processes and cochlear anoxia causes an almost immediate reduction in EP (Perlman et al. 1959; Thalman et al. 1973).

    • 17β-Estradiol promotes angiogenesis of stria vascular in cochlea of C57BL/6J mice

      2021, European Journal of Pharmacology
      Citation Excerpt :

      The major vascular network involved in the blood supply is located in the lateral wall of the cochlea and regulates about 80% of the blood flow. These capillaries play a key role in controlling the transduction of sensory hair cells by regulating cochlea potential, ion transport, and lymphatic balance (Asakuma and Snow, 1980; Anniko and Wróblewski, 1986; Hellier et al., 2002; Patuzzi, 2011). Age-related hearing loss (ARHL) is the most common form of sensory disability, also known as presbycusis (Gates and Mills, 2005; Bowl and Dawson, 2015).

    View all citing articles on Scopus
    View full text