| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
RELATED PAPERS |
1 University of Tübingen, Department of Otorhinolaryngology, Tübingen Hearing Research Centre (THRC), Molecular Neurobiology, Elfriede-Aulhorn-Str. 5, D-72076 Tübingen, Germany
2 Biochemical Institute, Christian-Albrechts-University Kiel, D-24098 Kiel, Germany
3 Anatomical Institute, Christians-Albrecht-University Kiel, D-24098 Kiel, Germany
4 University of Helsinki, Department of Biological and Environmental Sciences, 00014 Helsinki, Finland
Our previous studies revealed a critical role of the lysosomal membrane protein LIMP2 in the regulation of membrane transport processes in the endocytic pathway. Here we show that LIMP2-deficient mice display a progressive high-frequency hearing loss and decreased otoacoustic emissions as early as 4 weeks of age. In temporal overlap to hearing impairment, fluorescence immunohistochemical studies revealed that the potassium channel KCNQ1 and its ß-subunit KCNE1 were almost completely lost in the luminal part of marginal cells in the stria vascularis, affecting first higher and later also lower frequency processing cochlear turns. Concomitant with this, the expression of megalin, a multiligand endocytic receptor, was reduced in luminal surfaces of marginal cells within the stria vascularis. KCNQ1/KCNE1 and megalin were also lost in the dark cells of the vestibular system. Although LIMP2 is normally expressed in all cells of the stria vascularis, in the organ of Corti and cochlear neurons, the lack of LIMP2 preferentially caused a loss of KCNQ1/KCNE1 and megalin, and structural changes were only seen months later, indicating that these proteins are highly sensitive to disturbances in the lysosomal pathway. The spatio-temporal correlation of the loss of KCNQ1/KCNE1 surface expression and loss of hearing thresholds supports the notion that the decline of functional KCNQ1/KCNE1 is likely to be the primary cause of the hearing loss. Our findings suggest an important role for LIMP2 in the control of the localization and the level of apically expressed membrane proteins such as KCNQ1, KCNE1 and megalin in the stria vascularis.
(Received 11 July 2006;
accepted after revision 8 August 2006;
first published online 10 August 2006)
Corresponding author P. Saftig: Biochemical Institute, Christian-Albrechts-University Kiel, Olshausenstr. 40, D-24098 Kiel, Germany. Email: psaftig{at}biochem.uni-kiel.de
This article has been cited by other articles:
|
|
 |
|
  A. Balreira, P. Gaspar, D. Caiola, J. Chaves, I. Beirao, J. L. Lima, J. E. Azevedo, and M. C. S. Miranda A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome Hum. Mol. Genet., July 15, 2008; 17(14): 2238 - 2243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Konig, L. Ruttiger, M. Muller, U. Zimmermann, B. Erdmann, H. Kalbacher, M. Gross, and M. Knipper Estrogen and the inner ear: megalin knockout mice suffer progressive hearing loss FASEB J, February 1, 2008; 22(2): 410 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Lang, V. Vallon, M. Knipper, and P. Wangemann Functional significance of channels and transporters expressed in the inner ear and kidney Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1187 - C1208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Schroen, J. J. Leenders, A. van Erk, A. T. Bertrand, M. van Loon, R. E. van Leeuwen, N. Kubben, R. F. Duisters, M. W. Schellings, B. J. Janssen, et al. Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy J. Exp. Med., May 14, 2007; 204(5): 1227 - 1235. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
