2001 Fiscal Year Final Research Report Summary
Intracellura traffic king of channel proteins and its regulation
| Project/Area Number |
12671027
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KUWAHARA Michio Tokyo Medical and Dental University, Dept. of Blood Purification, Associate Prof., 医学部・附属病院, 助教授 (60221230)
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| Co-Investigator(Kenkyū-buntansha) |
SASAKI Sei Tokyo Medical and Dental University, Dept. of Homeostasis Medicines and Nephrology, Associate Prof., 大学院・医歯学総合研究科, 助教授 (60170677)
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| Project Period (FY) |
2000 – 2001
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| Keywords | trafficking / sorting signal / AQP2 / nephrogenic diabetes insipidus |
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| Research Abstract |
1. We analyzed three cases of autosomal dominant nephrogenic diabetes insipidus (NDI) caused by the AQP2 water channel gene mutations. The mutations were found in the C-terminus Our results suggest that the trafficking of mutant AQP2 is impaired due to elongation of the C-terminal tail, and the dominant negative effect is attributed to oligomerization of the wild-type and mutant AQP2s. Therefore, the C-terminus of AQP2 may be important for the intracellular trafficking of AQP2 protein.
2. The wild-type AQP2 proteins form tetramers, whereas it has been suggested that the mutant AQP2s causing autosomal recessive NDI retain in endoplasmic reticulum as a monomer. However, our results suggested that these mutant AQP2s also form mixed tetramers with the wild-type AQP2.
3. We found that the F40F9.9 gene in C. Elegans encodes a water channel protein and designated this protein as AQP-CE2.
4. Mixed oligomers of the wild-type AQP2 and mutant AQP2 causing autosomal dominant NDI are mistargeted to the basolateral membrane due to the dominant negative effect of the mutant. The mistargeting of the apical membrane protein to the basolateral membrane is a novel molecular pathogenesis of hereditary diseases.
5. We obtained several findings in the field of the intracellular signal transduction.
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[Publications] Kuwahara M., Iwai K., Ooeda T., Igarashi T., Ogawa E., Katsushima Y, Shinbo I, Uchida S., Terada Y., Fujiwara T.M., Arthus M.-F, Lonergan M, Bichet D.G., Marumo F, and Sasaki S.: "Three families with autosomal dominant nephrogenic diabetes insipidus caused by aquaporin-2 mutations in the C-terminus"Am. J. Hum. Genet. 69. 738-748 (2001)
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