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

2000; Elsevier BV; Volume: 78; Issue: 6 Linguagem: Inglês

10.1016/s0006-3495(00)76830-5

1542-0086

H. Monoi, Shiroh Futaki, Shinichi Kugimiya, Hiroyuki Minakata, Kazuo Yoshihara,

Mitochondrial Function and Pathology

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.