Bimodal agonism: a new desensitization in a cyclic nucleotide-gated channel is coordinated by two adjacent binding domains

Cyclic nucleotide-gated (CNG) channels are activated by direct binding of cyclic nucleotide (CN) to the binding domain (BD). How CN binding is coupled to channel opening remains unresolved. Bimodal agonism is found in the catfish olfactory CNGA2 subtype when cGMP is the agonist: initial cGMP binding events activate the channel while additional cGMP binding events deactivate the channel. The C-terminal region of the BD was previously shown to determine ligand selectivity and efficacy; therefore, this region from the normal (non-bimodal) BD was substituted into the bimodal BD. Excised patch-clamp measurements suggest that this region is not essential in bimodal agonism. We found a tandem tetramer with two adjacent bimodal pseudo-subunits can produce bimodal agonism whereas a tetramer with two diagonally opposing bimodal pseudo-subunits cannot. This implies that bimodal agonism does not require four bimodal BDs and the additional cGMP binding is coordinated by two adjacent bimodal BDs.