Poly-(L)-glutamine forms cation channels: Relevance to the pathogenesis ofthe polyglutamine diseases

Citation
H. Monoi et al., Poly-(L)-glutamine forms cation channels: Relevance to the pathogenesis ofthe polyglutamine diseases, BIOPHYS J, 78(6), 2000, pp. 2892-2899
Citations number
45
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOPHYSICAL JOURNAL
ISSN journal
00063495 → ACNP
Volume
78
Issue
6
Year of publication
2000
Pages
2892 - 2899
Database
ISI
SICI code
0006-3495(200006)78:6<2892:PFCCRT>2.0.ZU;2-F
Abstract
We report that long-chain poly-L-glutamine forms cation-selective channels when incorporated into artificial planar lipid bilayer membranes. The chann el was permeable to alkali cations and H+ ions and virtually impermeable to anions; the selectivity sequence based on the single-channel conductance w as H+ much greater than Cs+ > K+ > Na+. The cation channel was characterize d by long-lived open states (often lasting for several minutes to tens of m inutes) interrupted by brief closings. The appearance of the channel depend ed critically on the length of polyglutamine chains; ion channels were obse rved 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 mechan ics calculation suggests a mu-helix (Monoi, 1995. Biophys. J. 69:1130-1141) as a candidate molecular structure of the channel. The channel-forming nat ure of long-chain poly-L-glutamine may provide a clue to the elucidation of the pathogenetic mechanism of the polyglutamine diseases, a group of inher ited neurodegenerative disorders including Huntington's disease.