Nonlinear amplification by calcium-dependent chloride channels in olfactory receptor cells

Abstract

The sense of smell is highly evolved in mammals, allowing discrimination between a vast number of odorants, with detection thresholds as low as 10(-17) M (ref. 1). Although several features of mammalian olfactory transduction have been revealed by biochemical and molecular biological studies, the odorant-induced membrane current has remained elusive. In amphibians this current is mediated by cyclic-nucleotide-gated channels, which depolarize the cell by Na+ and Ca+ influx and consequent Cl- efflux through Ca(2+)-dependent Cl- channels. The Cl- current may be absent in mammals, however, because its proposed role is linked to the aquatic habitat of amphibians. Here we show that the transduction current in rat olfactory receptor cells is initiated by cyclic-nucleotide-gated channels. The Cl- current is also present and endows the transduction current with a steep sigmoidal dependence on cyclic AMP concentration in both rat and in an amphibian, indicating a new function for the Cl- channel: nonlinear amplification of the transduction signal, whereby suprathreshold responses are boosted relative to basal transduction noise.

Ca2+-activated Cl− currents are dispensable for olfaction

“…By contrast, the cation concentration in the mucus surrounding olfactory cilia in mammals 14,15 allows for a sizeable depolarization when CNG channels open upon an odorant-induced rise in cAMP. After first publications had shown that Ca 2+ -activated Cl -currents could powerfully amplify olfactory receptor currents [4][5][6][7] , this concept has received support from many groups. Experiments with isolated receptor neurons [4][5][6]8 showed that up to 80-90% of the receptor current is carried by Cl -.…”

“…After first publications had shown that Ca 2+ -activated Cl -currents could powerfully amplify olfactory receptor currents 4-7 , this concept has received support from many groups. Experiments with isolated receptor neurons [4][5][6]8 showed that up to 80-90% of the receptor current is carried by Cl -. An important role for Cl -in olfaction was also inferred from EOGs 11,16,37 .…”

“…The superfusate could be switched to a solution containing niflumic acid (NFA). NFA has been widely used to block Ca 2+ -activated Cl -channels in OSNs and other 6 cells 4,6,9,11,16,34,36,37 and inhibits both Ano1 and Ano2 18,20,21,33,34 . The response to odorants was reduced by roughly 40% in Ano2 -/-EOGs compared to the wild type (Fig.…”

“…cAMP then opens heteromeric cyclic nucleotide-gated (CNG) cation channels 3 . The resulting influx of Na + and Ca 2+ depolarizes the plasma membrane and raises the cytosolic Ca 2+ concentration ([Ca 2+ ] i ), thereby activating Ca 2+ -activated Cl -channels 1,[4][5][6][7][8][9][10] . All these components of the signal transduction cascade are localized to sensory cilia, which are embedded in the mucus covering the MOE.…”

“…There has been broad consensus that Ca 2+ -activated Cl -channels powerfully amplify olfactory signal transduction 1,[4][5][6][7][8][9][10] . These channels are thought to mediate an outward flow of Cl -, which generates a depolarizing current that, in rodents, is five-to tenfold larger than currents through CNG channels 8,11,12 .…”