Human Molecular Genetics Advance Access published online on February 3, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp024
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The Multimeric Structure of Polycystin-2 (TRPP2): Structural-Functional Correlates of Homo- and Hetero-multimers with TRPC1
1 Nephrology Division & Electrophysiology Core, Massachusetts General Hospital East, Charlestown, MA, 02129 and Department of Medicine, Harvard Medical School, Boston, MA, 02115 USA 2 Laboratorio de Canales Iónicos, ININCA, UBA-CONICET, Buenos Aires, 1122AAJ, Argentina 3 Renal Division, Department of Medicine, Brigham's and Women's Hospital, and Harvard Medical School, Boston, MA, 02115 USA 4 Physics Department, Boston University, Boston, MA, 02115
* Address correspondence to: Horacio F. Cantiello, Nephrology Division & Electrophysiology Core, Massachusetts General Hospital East, 149 13th Street, Charlestown, MA 02129, Tel: 617-7265640; Fax: 617-7265669; Email: cantiello{at}helix.mgh.harvard.edu
Received November 10, 2008; Revised January 12, 2009; Accepted January 12, 2009
Polycystin-2 (PC2, TRPP2), the gene product of PKD2, whose mutations cause autosomal dominant polycystic kidney disease (ADPKD), belongs to the superfamily of TRP channels. PC2 is a non-selective cation channel, with multiple subconductance states. In this report, we explored structural and functional properties of PC2 and whether the conductance substates represent monomeric contributions to the channel complex. A kinetic analysis of spontaneous channel currents of PC2 showed that four intrinsic, non-stochastic sub-conductance states, which followed a staircase behavior, were both pH-, and voltage-dependent. To confirm the oligomeric contributions to PC2 channel function, heteromeric PC2/TRPC1 channel complexes were also functionally assessed by single channel current analysis. Low pH inhibited the PC2 currents in PC2 homomeric complexes, but failed to affect PC2 currents in PC2/TRPC1 heteromeric complexes. Amiloride, in contrast, abolished PC2 currents in both the homomeric PC2 complexes and the heteromeric PC2/TRPC1 complexes, thus PC2/TRPC1 complexes have distinct functional properties from the homomeric complexes. The topological features of the homomeric PC2-, TRPC1-, and heteromeric PC2/TRPC1 channel complexes, assessed by atomic force microscopy (AFM), were consistent with structural tetramers. TRPC1 homomeric channels had different average diameter and protruding height as compared to the PC2 homomers. The contribution of individual monomers to the PC2/TRPC1 hetero-complexes was easily distinguishable. The data support tetrameric models of both the PC2 and TRPC1 channels, where the overall conductance of a particular channel will depend on the contribution of the various functional monomers in the complex.
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