Cyclic-nucleotide–gated cation current and Ca2+-activated Cl current elicited by odorant in vertebrate olfactory receptor neurons

Olfactory transduction in vertebrate olfactory receptor neurons (ORNs) involves primarily a cAMP-signaling cascade that leads to the opening of cyclic-nucleotide–gated (CNG), nonselective cation channels. The consequent Ca2+ influx triggers adaptation but also signal amplification, the latter by opening a Ca2+-activated Cl channel (ANO2) to elicit, unusually, an inward Cl current. Hence the olfactory response has inward CNG and Cl components that are in rapid succession and not easily separable. We report here success in quantitatively separating these two currents with respect to amplitude and time course over a broad range of odorant strengths. Importantly, we found that the Cl current is the predominant component throughout the olfactory dose–response relation, down to the threshold of signaling to the brain. This observation is very surprising given a recent report by others that the olfactory-signal amplification effected by the Ca2+-activated Cl current does not influence the behavioral olfactory threshold in mice.

Download Full-text

Adaptive integrate-and-fire model reproduces the dynamics of olfactory receptor neuron responses in a moth

Journal of The Royal Society Interface ◽

10.1098/rsif.2019.0246 ◽

2019 ◽

Vol 16 (157) ◽

pp. 20190246 ◽

Cited By ~ 1

Author(s):

Marie Levakova ◽

Lubomir Kostal ◽

Christelle Monsempès ◽

Philippe Lucas ◽

Ryota Kobayashi

Keyword(s):

Olfactory Receptor ◽

Time Course ◽

Olfactory Receptor Neuron ◽

Receptor Activation ◽

Olfactory Receptor Neurons ◽

Response Dynamics ◽

Spike Threshold ◽

Olfactory Stimuli ◽

Receptor Neurons ◽

The Brain

In order to understand how olfactory stimuli are encoded and processed in the brain, it is important to build a computational model for olfactory receptor neurons (ORNs). Here, we present a simple and reliable mathematical model of a moth ORN generating spikes. The model incorporates a simplified description of the chemical kinetics leading to olfactory receptor activation and action potential generation. We show that an adaptive spike threshold regulated by prior spike history is an effective mechanism for reproducing the typical phasic–tonic time course of ORN responses. Our model reproduces the response dynamics of individual neurons to a fluctuating stimulus that approximates odorant fluctuations in nature. The parameters of the spike threshold are essential for reproducing the response heterogeneity in ORNs. The model provides a valuable tool for efficient simulations of olfactory circuits.

Download Full-text

Ca2+-activated Cl current predominates in threshold response of mouse olfactory receptor neurons

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1803443115 ◽

2018 ◽

Vol 115 (21) ◽

pp. 5570-5575 ◽

Cited By ~ 6

Author(s):

Rong-Chang Li ◽

Chih-Chun Lin ◽

Xiaozhi Ren ◽

Jingjing Sherry Wu ◽

Laurie L. Molday ◽

...

Keyword(s):

Olfactory Receptor ◽

Signal Amplification ◽

Olfactory Receptor Neurons ◽

Behavioral Threshold ◽

Olfactory Transduction ◽

Threshold Response ◽

Axonal Projections ◽

Cl Channels ◽

Receptor Neurons ◽

The Brain

In mammalian olfactory transduction, odorants activate a cAMP-mediated signaling pathway that leads to the opening of cyclic nucleotide-gated (CNG), nonselective cation channels and depolarization. The Ca2+ influx through open CNG channels triggers an inward current through Ca2+-activated Cl channels (ANO2), which is expected to produce signal amplification. However, a study on an Ano2−/− mouse line reported no elevation in the behavioral threshold of odorant detection compared with wild type (WT). Subsequent studies by others on the same Ano2−/− line, nonetheless, found subtle defects in olfactory behavior and some abnormal axonal projections from the olfactory receptor neurons (ORNs) to the olfactory bulb. As such, the question regarding signal amplification by the Cl current in WT mouse remains unsettled. Recently, with suction-pipette recording, we have successfully separated in frog ORNs the CNG and Cl currents during olfactory transduction and found the Cl current to predominate in the response down to the threshold of action-potential signaling to the brain. For better comparison with the mouse data by others, we have now carried out similar current-separation experiments on mouse ORNs. We found that the Cl current clearly also predominated in the mouse olfactory response at signaling threshold, accounting for ∼80% of the response. In the absence of the Cl current, we expect the threshold stimulus to increase by approximately sevenfold.

Download Full-text

Anomalous mole–fraction effects in recombinant and native cyclic nucleotide–gated channels in rat olfactory receptor neurons

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2001.1663 ◽

2001 ◽

Vol 268 (1474) ◽

pp. 1395-1403 ◽

Cited By ~ 5

Author(s):

W. Qu ◽

A. J. Moorhouse ◽

A. M. Cunningham ◽

P. H. Barry

Keyword(s):

Mole Fraction ◽

Cyclic Nucleotide ◽

Olfactory Receptor ◽

Olfactory Receptor Neurons ◽

Cyclic Nucleotide Gated Channels ◽

Receptor Neurons

Download Full-text

Divalent cations block the cyclic nucleotide-gated channel of olfactory receptor neurons

Journal of Neurophysiology ◽

10.1152/jn.1993.69.5.1758 ◽

1993 ◽

Vol 69 (5) ◽

pp. 1758-1768 ◽

Cited By ~ 64

Author(s):

F. Zufall ◽

S. Firestein

Keyword(s):

Cyclic Amp ◽

Calcium Channels ◽

Cyclic Nucleotide ◽

Olfactory Receptor ◽

Single Channel ◽

Divalent Cations ◽

Olfactory Receptor Neurons ◽

Gated Channel ◽

Receptor Neurons ◽

Single Channel Currents

1. The effects of external divalent cations on odor-dependent, cyclic AMP-activated single-channel currents from olfactory receptor neurons of the tiger salamander (Ambystoma tigrinum) were studied in inside-out membrane patches taken from dendritic regions of freshly isolated sensory cells. 2. Channels were reversibly activated by 100 microM cyclic AMP. In the absence of divalent cations, the channel had a linear current-voltage relation giving a conductance of 45 pS. With increasing concentrations of either Ca2+ or Mg2+ in the external solution, the channel displayed a rapid flickering behavior. At higher concentrations of divalent cations, the transitions were too rapid to be fully resolved and appeared as a reduction in mean unitary single-channel current amplitude. 3. This effect was voltage dependent, and on analysis was shown to be due to an open channel block by divalent ions. In the case of Mg2+, the block increased steadily with hyperpolarization. In contrast, for Ca2+ the block first increased with hyperpolarization and then decreased with further hyperpolarization beyond -70 mV, providing evidence for Ca2+ permeation of this channel. 4. This block is similar to that seen in voltage-gated calcium channels. Additionally, the cyclic nucleotide-gated channel shows some pharmacological similarities with L-type calcium channels, including a novel block of the cyclic nucleotide channel by nifedipine (50 microM). 5. Our results indicate that the sensory generator current simultaneously depends on the presence of the second messenger and on the membrane potential of the olfactory neuron.

Download Full-text

Both External and Internal Calcium Reduce the Sensitivity of the Olfactory Cyclic-Nucleotide-Gated Channel to cAMP

Journal of Neurophysiology ◽

10.1152/jn.1999.81.6.2675 ◽

1999 ◽

Vol 81 (6) ◽

pp. 2675-2682 ◽

Cited By ~ 30

Author(s):

Steven J. Kleene

Keyword(s):

Cyclic Nucleotide ◽

Olfactory Receptor ◽

Electrical Signal ◽

Olfactory Receptor Neurons ◽

Unexpected Result ◽

Patch Clamp Recording ◽

Ciliary Membrane ◽

Gated Channel ◽

Receptor Neurons ◽

Internal Calcium

Both external and internal calcium reduce the sensitivity of the olfactory cyclic-nucleotide-gated channel to cAMP. In vertebrate olfaction, odorous stimuli are first transduced into an electrical signal in the cilia of olfactory receptor neurons. Many odorants cause an increase in ciliary cAMP, which gates cationic channels in the ciliary membrane. The resulting influx of Ca2+ and Na+ produces a depolarizing receptor current. Modulation of the cyclic-nucleotide-gated (CNG) channels is one mechanism of adjusting olfactory sensitivity. Modulation of these channels by divalent cations was studied by patch-clamp recording from single cilia of frog olfactory receptor neurons. In accord with previous reports, it was found that cytoplasmic Ca2+ above 1 μM made the channels less sensitive to cAMP. The effect of cytoplasmic Ca2+ was eliminated by holding the cilium in a divalent-free cytoplasmic solution and was restored by adding calmodulin (CaM). An unexpected result was that external Ca2+ could also greatly reduce the sensitivity of the channels to cAMP. This reduction was seen when external Ca2+ exceeded 30 μM and was not affected by the divalent-free solution, by CaM, or by Ca2+ buffering. The effects of cytoplasmic and external Ca2+ were additive. Thus the effects of cytoplasmic and external Ca2+ are apparently mediated by different mechanisms. There was no effect of CaM on a Ca2+-activated Cl− current that also contributes to the receptor current. Increases in Ca2+ concentration on either side of the ciliary membrane may influence olfactory adaptation.

Download Full-text