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Human Molecular Genetics Advance Access originally published online on April 20, 2005
Human Molecular Genetics 2005 14(12):1587-1603; doi:10.1093/hmg/ddi167
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Alpha-actinin associates with polycystin-2 and regulates its channel activity

Qiang Li1,{dagger}, Nicolás Montalbetti2,{dagger}, Patrick Y. Shen1, Xiao-Qing Dai1, Christopher I. Cheeseman1, Edward Karpinski1, Guanqing Wu3, Horacio F. Cantiello2,4 and Xing-Zhen Chen1,*

1Membrane Protein Research Group, Department of Physiology, University of Alberta, Edmonton, Alberta, T6G 2H7 Canada, 2Laboratorio de Canales Iónicos, Departamento de Fisicoquímica y Química Analítica, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina, 3Department of Medicine, Vanderbilt University, Nashville, TN 37232-0275, USA and 4Renal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA

* To whom correspondence should be addressed at: Department of Physiology, University of Alberta, 7-29 Medical Sciences Building, Edmonton, Alberta, T6G 2H7 Canada. Tel: +1 7804922294; Fax: +1 7804928915; Email: xzchen{at}ualberta.ca

Received December 9, 2004; Revised February 8, 2005; Accepted April 7, 2005

Polycystin-2 (PC2) is the product of the PKD2 gene, which is mutated in 10–15% patients of autosomal dominant polycystic kidney disease (ADPKD). PC2 is an integral transmembrane protein and acts as a calcium-permeable cation channel. The functional modulation of this channel by other protein partners remains largely unknown. In the present study, using a yeast two-hybrid approach, we discovered that both intracellular N- and C-termini of PC2 associate with {alpha}-actinins, actin-binding and actin-bundling proteins important in cytoskeleton organization, cell adhesion, proliferation and migration. The PC2-{alpha}-actinin association was confirmed by in vitro glutathione S-transferase pull-down and dot blot overlay assays. In addition, the in vivo interaction between endogenous PC2 and {alpha}-actinins was demonstrated by co-immunoprecipitation in human embryonic kidney 293 and Madin-Darby canine kidney (MDCK) cells, rat kidney and heart tissues and human syncytiotrophoblast (hST) apical membrane vesicles. Immunofluorescence experiments showed that PC2 and {alpha}-actinin were partially co-localized in epithelial MDCK and inner medullary collecting duct cells, NIH 3T3 fibroblasts and hST vesicles. We studied the functional modulation of PC2 by {alpha}-actinin in a lipid bilayer electrophysiology system using in vitro translated PC2 and found that {alpha}-actinin substantially stimulated the channel activity of reconstituted PC2. A similar stimulatory effect of {alpha}-actinin on PC2 was also observed when hST vesicles were reconstituted in lipid bilayer. Thus, physical and functional interactions between PC2 and {alpha}-actinin may play an important role in abnormal cell adhesion, proliferation and migration observed in ADPKD.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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