Abstract
BackgroundThe ionic composition of the luminal fluid in the vestibular labyrinth is maintained within tight limits by the many types of epithelial cells bounding the lumen. Regulatory mechanisms include systemic, paracrine and autocrine hormones along with their associated intracellular signal pathways. The epithelium lining the semicircular canal duct (SCCD) is a tissue that is known to absorb sodium and calcium and to secrete chloride.FindingsTransport function was assessed by measurements of short circuit current (Isc) and gene transcript expression was evaluated by microarray. Neither ATP nor UTP (100 microM) on the apical side of the epithelium had any effect on Isc. By contrast, basolateral ATP transiently increased Isc and transepithelial resistance dropped significantly after basolateral ATP and UTP. P2Y2 was the sole UTP-sensitive purinergic receptor expressed. Isc was reduced by 42%, 50% and 63% after knockdown of α-ENaC, stimulation of PKC and inhibition of PI3-K, while the latter two increased the transepithelial resistance. PKCdelta, PKCgamma and PI3-K were found to be expressed.ConclusionsThese observations demonstrate that ion transport by the SCCD is regulated by P2Y2 purinergic receptors on the basolateral membrane that may respond to systemic or local agonists, such as ATP and/or UTP. The sodium absorption from endolymph mediated by ENaC in SCCD is regulated by signal pathways that include the kinases PKC and PI3-K. These three newly-identified regulatory components may prove to be valuable drug targets in the control of pathologic vestibular conditions involving dysfunction of transport homeostasis in the ear, such as Meniere's disease.
Highlights
The transduction of linear and rotational acceleration into the sense of balance is driven and dependent on the ion composition of the luminal fluid, endolymph, of the vestibular labyrinth [1]
These observations demonstrate that ion transport by the semicircular canal duct (SCCD) is regulated by P2Y2 purinergic receptors on the basolateral membrane that may respond to systemic or local agonists, such as ATP and/or UTP
The sodium absorption from endolymph mediated by epithelial Na+ channels (ENaC) in SCCD is regulated by signal pathways that include the kinases protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3-K)
Summary
The transduction of linear and rotational acceleration into the sense of balance is driven and dependent on the ion composition of the luminal fluid, endolymph, of the vestibular labyrinth [1]. We have shown that the semicircular canal duct (SCCD) epithelium contributes to the homeostasis of endolymph by absorption of Na+, secretion of Cl- and absorption of Ca2+ [2,3,4]. These processes are known to be controlled by glucocorticoids, β-adrenergic agonists and vitamin D, respectively [2,3,4]. Na+ absorption is mediated by Na+ entry from endolymph into the SCCD cytosol via apical epithelial Na+ channels (ENaC) and removal of Na+ from the cytosol across the basolateral membrane by the "Na+-pump", Na+, K+-ATPase [2]. The epithelium lining the semicircular canal duct (SCCD) is a tissue that is known to absorb sodium and calcium and to secrete chloride
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