Tricellulin (also known as MARVELD2) is considered as a central component of tricellular tight junctions and is distributed among various epithelial tissues. Although mutations in the gene encoding tricellulin are known to cause deafness in humans (DFNB49) and mice, the influence of its systemic deletion in vivo remains unknown. When we generated tricellulin-knockout mice (Tric−/−), we found an early-onset rapidly progressive hearing loss associated with the degeneration of hair cells (HCs); however, their body size and overall appearance were normal. Tric−/− mice did not show any morphological change pertaining to other organs such as the gastrointestinal tract, liver, kidney, thyroid gland and heart. The endocochlear potential (EP) was normal in Tric−/− mice, suggesting that the tight junction barrier is maintained in the stria vascularis, where EP is generated. The degeneration of HCs, which occurred after the maturation of EP, was prevented in the culture medium with an ion concentration similar to that of the perilymph. These data demonstrate the specific requirement of tricellulin for maintaining ion homeostasis around cochlear HCs to ensure their survival. The Tric−/− mouse provides a new model for understanding the distinct roles of tricellulin in different epithelial systems as well as in the pathogenesis of DFNB49.
Ion transport and its regulation in the endolymphatic sac (ES) are reviewed on the basis of recent lines of evidence. The morphological and physiological findings demonstrate that epithelial cells in the intermediate portion of the ES are more functional in ion transport than those in the other portions. Several ion channels, ion transporters, ion exchangers, and so on have been reported to be present in epithelial cells of ES intermediate portion. An imaging study has shown that mitochondria-rich cells in the ES intermediate portion have a higher activity of Na+, K+-ATPase and a higher Na+ permeability than other type of cells, implying that molecules related to Na+ transport, such as epithelial sodium channel (ENaC), Na+–K+–2Cl− cotransporter 2 (NKCC2) and thiazide-sensitive Na+–Cl− cotransporter (NCC), may be present in mitochondria-rich cells. Accumulated lines of evidence suggests that Na+ transport is most important in the ES, and that mitochondria-rich cells play crucial roles in Na+ transport in the ES. Several lines of evidence support the hypothesis that aldosterone may regulate Na+ transport in ES, resulting in endolymph volume regulation. The presence of molecules related to acid/base transport, such as H+-ATPase, Na+–H+ exchanger (NHE), pendrin (SLC26A4), Cl−–HCO3 − exchanger (SLC4A2), and carbonic anhydrase in ES epithelial cells, suggests that acid/base transport is another important one in the ES. Recent basic and clinical studies suggest that aldosterone may be involved in the effect of salt-reduced diet treatment in Meniere’s disease.
To clarify the role of the endolymphatic sac (ES) in the regulation of endolymphatic pressure, the effects of isoproterenol, a -adrenergic receptor agonist, and acetazolamide, a potent carbonic anhydrase inhibitor, both of which decrease ES direct current potential on cochlear hydrostatic pressure, were examined in guinea pigs. When isoproterenol was applied intravenously, hydrostatic pressures of cochlear endolymph and perilymph were significantly increased with no change in endocochlear potential or the hydrostatic pressure of cerebrospinal fluid. Acetazolamide produced no marked change in the hydrostatic pressure of cochlear endolymph. In ears with an obstructed ES, the action of isoproterenol on the hydrostatic pressure of cochlear endolymph and perilymph was suppressed. These results suggest that the ES may regulate the hydrostatic pressure of the endolymphatic system via the action of the agents such as catecholamines on the ES. direct current potential; isoproterenol; acetazolamide THE ENDOLYMPHATIC SAC (ES), which is a part of the inner ear, is believed to absorb endolymph, since surgical blockage of the ES and the endolymphatic duct causes accumulation of endolymph in the cochlea and vestibule, as so-called endolymphatic hydrops (11), a characteristic pathological finding in Meniere's disease. Endolymphatic hydrops in the cochlea causes deafness, while endolymphatic hydrops in the vestibule causes vertigo (22, 31). Endolymph regulation is thus important for hearing and the sense of equilibrium (7,29). Although the ES is generally accepted to contain active ion transport systems and may absorb endolymph (11), no mechanisms of endolymph regulation by the ES have actually been established.ES direct current potential (ESP) and endocochlear direct current potential (EP) are known to be present in the ES and the cochlea, respectively (3, 12, 15). ESP and EP are generated by active ion transports in the ES and cochlea, respectively (3, 15, 21). ESP and EP can thus be used as indices of function for the ES and cochlea, respectively (15, 21). Catecholamines reportedly depress ESP through -adrenergic receptors (19). The finding that isoproterenol, a -adrenergic receptor agonist, at a dose of 12.5 g/kg decreases ESP without changing EP (16), suggests that isoproterenol would suppress active ion transport in the ES without inhibiting active ion transport in the cochlea. Acetazolamide, a potent carbonic anhydrase inhibitor, reportedly depresses ESP more sensitively than EP (32, 33). The result that cotreatment with isoproterenol and acetazolamide at doses producing near-maximum reduction of ESP depresses almost all parts of the ESP, suggesting that isoproterenol and acetazolamide may depress ESP via different mechanisms and that ESP may be composed of isoproterenol-and acetazolamide-sensitive parts (17).The ES has been hypothesized to regulate endolymphatic hydrostatic pressure (4, 9). However, no reports have described hydrostatic pressure regulation by the ES, as direct measurement of endolymphatic hydrostatic ...
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