ReviewIon flow in stria vascularis and the production and regulation of cochlear endolymph and the endolymphatic potential
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)
- et al.
Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf
J. Biol. Chem.
(1999) Gap junctions in the stria vascularis and effects of ethacrynic acid
Hear. Res.
(1984)- et al.
Electrochemical profiles for monovalent ions in the stria vascularis: cellular model of ion transport mechanisms
Hear. Res.
(1989) - et al.
Electrochemical profiles for calcium ions in the stria vascularis: cellular model of calcium transport mechanisms
Hear. Res.
(1989) - et al.
Early effects of acetozolamide on anionic activities of the guinea pig endolymph: evidence for active function of carbonic anhydrase in the cochlea
Hear. Res.
(1987) - et al.
The Ca activity of cochlear endolymph of the guinea pig and the effect of inhibitors
Hear. Res.
(1987) Forefront of Na+/Ca2+ exchanger studies: molecular pharmacology of Na+/Ca2+ inhibitors
J. Pharmacol. Sci.
(2004)- et al.
Cellular localization of Na+, K+-ATPase in the mammalian cochlear duct: significance for cochlear fluid balance
Am. J. Otolaryngol.
(1982) - et al.
The gap junction communication channel
Cell
(1996) - et al.
Endolymphatic sodium homeostasis by Reissner’s membrane
Neuroscience
(2003)
Potassium secretion by vestibular dark cell epithelium demonstrated by vibrating probe
Biophysical J.
Transepithelial voltage and resistance of vestibular dark cell epithelium from the gerbil ampulla
Hear. Res.
Sidedness of action of loop diuretics and ouabain on nonsensory cells of utricle: a micro-Ussing chamber for inner ear tissues
Hear. Res.
Changes in cation contents of stria vascuiaris with ouabain and potassium-free perfusion
Hear. Res.
Effects of barium and ion substitution in artificial blood on endocochlear potential
Hear. Res.
Response of cochlear potentials to presumed alterations of ionic conductance: endolymphatic perfusion of barium, valinomycin and nystatin
Hear. Res.
Protein kinase C mediates P2U purinergic receptor inhibition of K+ channel in apical membrane of strial marginal cells
Hear. Res.
K+ and Na+ absorption by outer sulcus epithelial cells
Hear. Res.
Electrophysiologicai measurements of the stria vascularis potentials in vivo
Hear. Res.
Permeability to chloride ions of the cochlear partition in normal guinea pigs
Hear. Res.
Outward rectifying potassium currents are the dominant voltage activated currents present in Deiters’ cell
Hear. Res.
KCNQ1/KCNE1 potassium channels in mammalian vestibular dark cells
Hear. Res.
Positive endocochlear potential: mechanism of production by marginal cells of stria vascularis
Hear. Res.
Ultrastructure of the inner ear of NKCC1-deficient mice
Hear. Res.
From deafness genes to hearing mechanisms: harmony and counterpoint
Trends Mol. Med.
The time course of the strial changes produced by intravenous furosemide
Hear. Res.
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.
Freeze-fracturing of the human stria vascularis
Acta Otolaryngol. (Stockh)
Sodium/Calcium exchange: its physiological implications
Physiol. Rev.
Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold
EMBO J.
The nature of the negative endocochlear potentials produce by anoxia and ethacrynic acid in the rat and the guinea pig
J. Physiol.
The nature of the ototoxic actions of ethacrynic acid upon the mammalian endolymph system: 1. Functional Aspects
Acta Otolaryngol.
The nature of the ototoxic actions of ethacrynic acid upon the mammalian endolymph system: 2.Structural-functional correlates in the stria vascularis
Acta Otolaryngol.
The nature of the ototoxic actions of ethacrynic acid upon mammalian endolymph system
Arch. Otorhinolaryngol.
Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions
J. Cell. Mol. Med.
Effects of mutations at the W locus (c-kit) on inner ear pigmentation and function in the mouse
Pigment Cell Res.
Exon loss accounts for differential sorting of Na-K-Cl cotransporters in polarized epithelial cells
Mol. Biol. Cell
Thermodynamics and kinetics of electrogenic pumps
Resting membrane potential of the strial cells of the guinea pig
Experientia
Connexins responsible for hereditary deafness: the tale unfolds
Electrogenic pumps: Theoretical and practical considerations
Mutation of the Na-K-CI co-transporter gene SIc12a2 results in deafness in mice
Hum. Mol. Genet.
Ca2+ signaling in Deiters cells of the guinea-pig cochlea: active process in supporting cells?
Mannitol-induced stria vascularis edema
Arch. Otolaryngol.
Development of 4-AP and TEA sensitivities in mammalian myelinated nerve fibers
J. Neurophys
Barttin is a Cl-channel beta-subunit crucial for renal Cl− reabsorption and inner ear K+ secretion
Nature
Ion permeation and selectivity in ClC-type chloride channels
Am. J. Physiol.
Assessment of ultrastructure in isolated cochlear hair cells using a procedure for rapid freezing before freeze-fracture and deep-etching
J. Neurocytol.
A kinetic study of the Na pump in red cells: its relevance to the mechanism of active transport. Ann N
Y. Acad. Sci.
Characteristics and regulatory mechanisms of the amiloride-blockable Na+ channel
Physiol. Revs
Cited by (70)
The role of the stria vascularis in neglected otologic disease
2023, Hearing ResearchCitation 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).
AAV8BP2 and AAV8 transduce the mammalian cochlear lateral wall and endolymphatic sac with high efficiency
2022, Molecular Therapy Methods and Clinical DevelopmentIdentifying targets to prevent aminoglycoside ototoxicity
2022, Molecular and Cellular NeuroscienceHearing loss caused by CMV infection is correlated with reduced endocochlear potentials caused by strial damage in murine models
2022, Hearing ResearchCitation 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 PharmacologyCitation 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).