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J. Biol. Chem., Vol. 279, Issue 24, 25582-25589, June 11, 2004

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The N-terminal Extracellular Domain Is Required for Polycystin-1-dependent Channel Activity^*

Victor Babich, Wei-Zhong Zeng, Byung-Il Yeh, Oxana Ibraghimov-Beskrovnaya¶, Yiqiang Cai||, Stefan Somlo||, and Chou-Long Huang**

From the Division of Nephrology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, ^¶Genomics and Genetics, Genzyme Corp. Framingham, Massachusetts 01701, and the ^||Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06519

Autosomal dominant polycystic kidney disease (PKD) is caused by mutation of polycystin-1 or polycystin-2. Polycystin-2 is a Ca²⁺-permeable cation channel. Polycystin-1 is an integral membrane protein of less defined function. The N-terminal extracellular region of polycystin-1 contains potential motifs for protein and carbohydrate interaction. We now report that expression of polycystin-1 alone in Chinese hamster ovary (CHO) cells and in PKD2-null cells can confer Ca²⁺-permeable non-selective cation currents. Co-expression of a loss-of-function mutant of polycystin-2 in CHO cells does not reduce polycystin-1-dependent channel activity. A polycystin-1 mutant lacking 2900 amino acids of the extracellular region is targeted to the cell surface but does not produce current. Extracellular application of antibodies against the immunoglobulin-like PKD domains reduces polycystin-1-dependent current. These results support the hypothesis that polycystin-1 is a surface membrane receptor that transduces the signal via changes in ionic currents.

Received for publication, March 12, 2004 , and in revised form, April 1, 2004.

^* This work was supported by grants from the National Institutes of Health, American Heart Association, Polycystic Kidney Research Foundation, and Kidney Texas Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work and are listed in alphabetic order.

^** To whom correspondence should be addressed: Dept. of Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8856. Tel.: 214-648-8627; Fax: 214-648-2071; E-mail: chou-long.huang{at}UTSouthwestern.edu.

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