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

Abstract

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 Ca²⁺ 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 rat¹⁹ 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 Ca²⁺ -triggered olfactory adaptation.