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Three amino acids in the C‐linker are major determinants of gating in cyclic nucleotide‐gated channels

The activation of cyclic nucleotide‐gated (CNG) channels is a complex process comprising the initial ligand binding and a consecutive allosteric transition from a closed to an open configuration. The cone and olfactory CNG channels differ considerably in cyclic nucleotide affinity and efficacy. In each channel, the cyclic nucleotide‐binding site is connected to the last transmembrane segment of the channel by a linker peptide (C‐linker) of ∼90 amino acids. Here we report that replacement of three amino acids in the cone C‐linker by the corresponding amino acids of the olfactory channel (I439V, D481A and D494S) profoundly enhanced the cAMP efficacy and increased the affinities for cAMP and cGMP. Unlike the wild‐type cone channel, the mutated channel exhibited similar single‐channel kinetics for both cGMP and cAMP, explaining the increase in cAMP efficacy. We thus conclude that the identified amino acids are major determinants of channel gating.