Interdomain Interactions Underlying Activation of Cyclic Nucleotide-Gated Channels

Abstract

Cyclic nucleotide–gated (CNG) ion channels are multimeric proteins that activate in response to the binding of cyclic nucleotide to intracellular domains. Here, an intramolecular protein–protein interaction between the amino-terminal domain and the carboxyl-terminal ligand-binding domain of the rat olfactory CNG channel was shown to exert an autoexcitatory effect on channel activation. Calcium-calmodulin, which modulates CNG channel activity during odorant adaptation, blocked this interaction. A specific deletion within the amino-terminal domain disrupted the interdomain interaction in vitro and altered the gating properties and calmodulin sensitivity of expressed channels. Thus, the amino-terminal domain may promote channel opening by directly interacting with the carboxyl-terminal gating machinery; calmodulin regulates channel activity by targeting this interaction.