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Biophys J, June 2000, p. 2892-2899, Vol. 78, No. 6

Poly-L-Glutamine Forms Cation Channels: Relevance to the Pathogenesis of the Polyglutamine Diseases

Hiroshi Monoi,*dagger Shiroh Futaki,Dagger Shin-ichi Kugimiya,§ Hiroyuki Minakata, and Kazuo Yoshihara

 *Research Institute of Neurodegenerative Diseases, Sendai 980-0871;  dagger Department of Physiology, Tohoku University School of Medicine, Sendai 980-0972;  Dagger Institute for Chemical Research, Kyoto University, Uji 611-0011;  §Graduate School of Material Science, Nara Institute of Science and Technology, Ikoma 630-0101; and  Suntory Institute for Bioorganic Research, Osaka 618-8503, Japan

We report that long-chain poly-L-glutamine forms cation-selective channels when incorporated into artificial planar lipid bilayer membranes. The channel was permeable to alkali cations and H+ ions and virtually impermeable to anions; the selectivity sequence based on the single-channel conductance was H+ Cs+ > K+ > Na+. The cation channel was characterized by long-lived open states (often lasting for several minutes to tens of minutes) interrupted by brief closings. The appearance of the channel depended critically on the length of polyglutamine chains; ion channels were observed with 40-residue stretches, whereas no significant conductance changes were detected with 29-residue tracts. The channel-forming threshold length of poly-L-glutamine was thus between 29 and 40 residues. A molecular mechanics calculation suggests a µ-helix (Monoi, 1995. Biophys. J. 69:1130-1141) as a candidate molecular structure of the channel. The channel-forming nature of long-chain poly-L-glutamine may provide a clue to the elucidation of the pathogenetic mechanism of the polyglutamine diseases, a group of inherited neurodegenerative disorders including Huntington's disease.

Biophys J, June 2000, p. 2892-2899, Vol. 78, No. 6
© 2000 by the Biophysical Society   0006-3495/00/06/2892/08  $2.00


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