Direct modulation by Ca²⁺-calmodulin of cyclic nucleotide-activated channel of rat olfactory receptor neurons

OLFACTORY receptor neurons depolarize in response to odorant stimulation of their sensory cilia^1-3. One transduction mechanism involves a G-protein-mediated increase in adenylate cyclase activity^4-8, raising the internal cyclic AMP concentration to open a cyclic nucleotide-activated cation channel on the plasma membrane^9-14. An influx of Ca ²⁺ through this channel, which is permeable to both monovalent and divalent cations, triggers olfactory adaptation¹⁵. Previous work has indicated that at least part of this Ca²⁺ -mediated adaptation resides in the channel itself^15-17, but the mechanism remains unclear and controversial^16-18. Here we use the cloned channel from rat ¹⁹ expressed in a cell line and the native channel from rat olfactory receptor cells to show that Ca²⁺ reduces the apparent affinity of the channel for cAMP by up to 20-fold in the presence of calmodulin, an abundant protein in olfactory cilia²⁰. This decrease in apparent affinity appears to involve a direct interaction between Ca²⁺-calmodulin and the channel, and it can reduce the activation of the channel by cAMP by up to a few hundred-fold, suggesting that it may be a key component of the Ca ²⁺ -triggered olfactory adaptation.