Poly-L-glutamine forms cation channels: relevance to the pathogenesis of the polyglutamine diseases.
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 mu-helix (. 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.
Monoi
H
H
Research Institute of Neurodegenerative Diseases, Sendai 980-0871, Japan. monoi@biology.is.tohoku.ac.jp
Futaki
S
S
Kugimiya
S
S
Minakata
H
H
Yoshihara
K
K
D002414:Cations, Monovalent / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels; D008051:Lipid Bilayers; D008081:Liposomes; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010455:Peptides / Q000737:chemistry* / Q000235:genetics*; D017433:Protein Structure, Secondary; D019680:Trinucleotide Repeat Expansion
D002414:Cations, Monovalent; D007473:Ion Channels; D008051:Lipid Bilayers; D008081:Liposomes; D010455:Peptides; C097188:polyglutamine