Protein mobility and GABA-induced conformational changes in GABAA receptor pore-lining M2 segment

Jeffrey Horenstein, David A. Wagner, Cynthia Czajkowski, Myles Akabas

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

Protein movements underlying ligand-gated ion channel activation are poorly understood. Here we used disulfide bond trapping to examine the proximity and mobility of cysteines substituted for aligned GABAA receptor α1 and β1 M2 segment channel-lining residues in resting and activated receptors. With or without GABA, disulfide bonds formed at α1N275C/β1E270C (20′) and α1S272C/β1H267C (17′), near the extracellular end, suggesting that this end is more mobile and/or flexible than the rest of the segment. Near the middle of M2, at α1T261C/β1T256C (6′), a disulfide bond formed only in the presence of GABA and locked the channels open. Channel activation must involve an asymmetric rotation of two adjacent subunits toward each other. This would move aligned engineered cysteines on different subunits into proximity and allow disulfide bond formation without blocking conduction. Asymmetric rotation of M2 segments is probably a common gating mechanism in other ligand-gated ion channels.

Original languageEnglish (US)
Pages (from-to)477-485
Number of pages9
JournalNature Neuroscience
Volume4
Issue number5
StatePublished - 2001

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GABA-A Receptors
Disulfides
gamma-Aminobutyric Acid
Ligand-Gated Ion Channels
Cysteine
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Protein mobility and GABA-induced conformational changes in GABAA receptor pore-lining M2 segment. / Horenstein, Jeffrey; Wagner, David A.; Czajkowski, Cynthia; Akabas, Myles.

In: Nature Neuroscience, Vol. 4, No. 5, 2001, p. 477-485.

Research output: Contribution to journalArticle

Horenstein, Jeffrey ; Wagner, David A. ; Czajkowski, Cynthia ; Akabas, Myles. / Protein mobility and GABA-induced conformational changes in GABAA receptor pore-lining M2 segment. In: Nature Neuroscience. 2001 ; Vol. 4, No. 5. pp. 477-485.
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