ALLOSTERIC ACTIVATION AND TUNING OF LIGAND EFFICACY IN CYCLIC-NUCLEOTIDE-GATED CHANNELS

Despite recent advances in the identification of ligand-binding(1,2) a nd voltage-sensing(3) regions of ion channels, the domains that couple such regions to channel opening have not been identified, Moreover, i t is uncertain whether ligand binding or depolarization are obligatory steps that must precede channel opening (according to linear reaction schemes(4,5)) or whether they act to stabilize the channel in an open state that can exist independently of ligand binding or depolarizatio n (according to cyclic allosteric models(6-8)), By comparing ligand-in dependent and ligand-dependent channel openings, we now show that reti nal and olfactory cyclic-nucleotide-gated channels(2) are activated by a cyclic allosteric mechanism, We further show that an amino-terminal domain, distinct from the pore and ligand-binding motifs, participate s in the allosteric gating transition, accounting for differences in t he free energy of gating of the two channels, The allosteric transitio n provides an important mechanism for tuning the physiological respons e of ligand-binding proteins, such as cyclic-nucleotidegated channels, to different biological signals.