Allosteric activation and tuning of ligand efficacy in cyclic- nucleotide-gated channels

Gareth R. Tibbs*, Evan H. Goulding, Steven A. Siegelbaum

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Despite recent advances in the identification of ligand-binding and voltage-sensing regions of ion channels, the domains that couple such regions to channel opening have not been identified. Moreover, it is uncertain whether ligand binding or depolarization are obligatory steps that must precede channel opening (according to linear reaction schemes) or whether they act to stabilize the channel in an open state that can exist independently of ligand binding or depolarization (according to cyclic allosteric models). By comparing ligand-independent and ligand-dependent channel openings, we now show that retinal and olfactory cyclic-nucleotide- gated channels are activated by a cyclic allosteric mechanism. We further show that an amino-terminal domain, distinct from the pore and ligand- binding motifs, participates in the allosteric gating transition, accounting for differences in the free energy of gating of the two channels. The allosteric transition provides an important mechanism for tuning the physiological response of ligand-binding proteins, such as cyclic-nucleotide- gated channels, to different biological signals.

Original languageEnglish (US)
Pages (from-to)612-615
Number of pages4
JournalNature
Volume386
Issue number6625
DOIs
StatePublished - Apr 10 1997

ASJC Scopus subject areas

  • General

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