Localization and Functional Studies of Pendrin in the Mouse Inner Ear Provide Insight About the Etiology of Deafness in Pendred Syndrome

Abstract

Immunolocalization studies of mouse cochlea and vestibular end-organ were performed to study the expression pattern of pendrin, the protein encoded by the Pendred syndrome gene (PDS), in the inner ear. The protein was restricted to the areas composed of specialized epithelial cells thought to play a key role in regulating the composition and resorption of endolymph. In the cochlea, pendrin was abundant in the apical membrane of cells in the spiral prominence and outer sulcus cells (along with their root processes). In the vestibular end-organ, pendrin was found in the transitional cells of the cristae ampullaris, utriculi, and sacculi as well as in the apical membrane of cells in the endolymphatic sac. Pdsknockout (Pds )/) ) mice were found to lack pendrin immunoreactivity in all of these locations. Histological studies revealed that the stria vascularis in Pds )/) mice was only two-thirds the thickness seen in wildtype mice, with the strial marginal cells showing irregular shapes and sizes. Functional studies were also performed to examine the role of pendrin in endolymph homeostasis. Using double-barreled electrodes placed in both the cochlea and the utricle, the endocochlear potential and endolymph potassium concentration were measured in wild-type and Pdsmice. Consistent with the altered strial morphology, the endocochlear potential in Pds )/) mice was near zero and did not change during anoxia. On the other hand, the endolymphatic potassium concentration in Pds )/) mice was near normal in the cochlea and utricle. Together, these results suggest that pendrin serves a key role in the functioning of the basal and/ or intermediate cells of the stria vascularis to maintain the endocochlear potential, but not in the potassium secretory function of the marginal cells.

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…Interestingly, KCNJ10 has also been described in the root cells of the outer sulcus, both in the adult rodent and human cochlea (Jagger et al, 2010; Eckhard et al, 2012). Also, the expression pattern of KCNJ10 that we observed in the outer sulcus during cochlear development matches the known expression pattern of PENDRIN in the outer sulcus of the adult mouse cochlea (Royaux et al, 2003; Wangemann et al, 2004). This provides a striking link between the two proteins and could help to explain the etiology of SNHL in Pendred syndrome.…”

Lack of pendrin HCO3−transport elevates vestibular endolymphatic [Ca2+] by inhibition of acid-sensitive TRPV5 and TRPV6 channels

“…However, the deletion of SLC26A4 had no effect on luminal (endolymphatic) [K + ] in the utricle (28), suggesting that neither the K + secretory channel in the apical membrane of vestibular dark cells nor K + exit pathways are strongly sensitive to luminal pH. However, the negative shift of the UP in Slc26a4 -/-mice is consistent with an increase in apical membrane conductance of highly polarized epithelial cells, such as the hair cells (17), as opposed to low-voltage K + -secretory dark cells (41).…”

The expression of wild-type pendrin (SLC26A4) in human embryonic kidney (HEK 293 Phoenix) cells leads to the activation of cationic currents

“…The detailed function of the SLC26A4 protein is still elusive. In the inner ear SLC26A4 seems to be involved in the conditioning of the endolymphatic fluid (26,27), and in the kidney it is involved in bicarbonate secretion (28 -30). In both cases, it is most probable that SLC26A4 is acting as a Cl 2 /HCO 3 2 exchanger.…”