scholarly journals Odorant Inhibition of the Olfactory Cyclic Nucleotide-gated Channel with a Native Molecular Assembly

2006 ◽  
Vol 128 (3) ◽  
pp. 365-371 ◽  
Author(s):  
Tsung-Yu Chen ◽  
Hiroko Takeuchi ◽  
Takashi Kurahashi
Keyword(s):  
Cyclic Nucleotide ◽  
Inhibitory Effect ◽  
Molecular Assembly ◽  
Definitive Evidence ◽  
Wide Range ◽  
Cng Channel ◽  
Gated Channel ◽  
Receptor Neurons ◽  
G Protein Coupled ◽  
Fine Tune

Human olfaction comprises the opposing actions of excitation and inhibition triggered by odorant molecules. In olfactory receptor neurons, odorant molecules not only trigger a G-protein–coupled signaling cascade but also generate various mechanisms to fine tune the odorant-induced current, including a low-selective odorant inhibition of the olfactory signal. This wide-range olfactory inhibition has been suggested to be at the level of ion channels, but definitive evidence is not available. Here, we report that the cyclic nucleotide-gated (CNG) cation channel, which is a key element that converts odorant stimuli into electrical signals, is inhibited by structurally unrelated odorants, consistent with the expression of wide-range olfactory inhibition. Interestingly, the inhibitory effect was small in the homo-oligomeric CNG channel composed only of the principal channel subunit, CNGA2, but became larger in channels consisting of multiple types of subunits. However, even in the channel containing all native subunits, the potency of the suppression on the cloned CNG channel appeared to be smaller than that previously shown in native olfactory neurons. Nonetheless, our results further showed that odorant suppressions are small in native neurons if the subsequent molecular steps mediated by Ca2+ are removed. Thus, the present work also suggests that CNG channels switch on and off the olfactory signaling pathway, and that the on and off signals may both be amplified by the subsequent olfactory signaling steps.

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

1993 ◽  
Vol 69 (5) ◽  
pp. 1758-1768 ◽  
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.

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

1999 ◽  
Vol 81 (6) ◽  
pp. 2675-2682 ◽  
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.

scholarly journals cGMP/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice

2015 ◽  
Vol 290 (34) ◽  
pp. 20880-20892 ◽  
Author(s):  
Hongwei Ma ◽  
Michael R. Butler ◽  
Arjun Thapa ◽  
Josh Belcher ◽  
Fan Yang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Er Stress ◽  
Cyclic Nucleotide ◽  
Protein Kinase G ◽  
Cng Channel ◽  
Inositol 1,4,5 Trisphosphate ◽  
Gated Channel ◽  
Trisphosphate Receptor ◽  
Deficient Mice

Photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. We have shown endoplasmic reticulum (ER) stress-associated apoptotic cone death and increased phosphorylation of the ER Ca2+ channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in CNG channel-deficient mice. We also presented a remarkable elevation of cGMP and an increased activity of the cGMP-dependent protein kinase (protein kinase G, PKG) in CNG channel deficiency. This work investigated whether cGMP/PKG signaling regulates ER stress and IP3R1 phosphorylation in CNG channel-deficient cones. Treatment with PKG inhibitor and deletion of guanylate cyclase-1 (GC1), the enzyme producing cGMP in cones, were used to suppress cGMP/PKG signaling in cone-dominant Cnga3−/−/Nrl−/− mice. We found that treatment with PKG inhibitor or deletion of GC1 effectively reduced apoptotic cone death, increased expression levels of cone proteins, and decreased activation of Müller glial cells. Furthermore, we observed significantly increased phosphorylation of IP3R1 and reduced ER stress. Our findings demonstrate a role of cGMP/PKG signaling in ER stress and ER Ca2+ channel regulation and provide insights into the mechanism of cone degeneration in CNG channel deficiency.

NO upregulation of a cyclic nucleotide-gated channel contributes to calcium elevation in endothelial cells

2002 ◽  
Vol 283 (4) ◽  
pp. C1080-C1089 ◽  
Author(s):  
Jianliang Zhang ◽  
Shen-Ling Xia ◽  
Edward R. Block ◽  
Jawaharlal M. Patel
Keyword(s):  
Endothelial Cells ◽  
Cyclic Nucleotide ◽  
Cytosolic Calcium ◽  
Calcium Entry ◽  
Mrna Levels ◽  
No Donor ◽  
Cng Channel ◽  
Gated Channel ◽  
Calcium Elevation ◽  
Porcine Pulmonary Artery

We investigated whether nitric oxide (NO) upregulates a cyclic nucleotide-gated (CNG) channel and whether this contributes to sustained elevation of intracellular calcium levels ([Ca2+]i) in porcine pulmonary artery endothelial cells (PAEC). Exposure of PAEC to an NO donor, NOC-18 (1 mM), for 18 h increased the protein and mRNA levels of CNGA2 40 and 50%, respectively ( P < 0.05). [Ca2+]iin NO-treated cells was increased 50%, and this increase was maintained for up to 12 h after removal of NOC-18 from medium. Extracellular calcium is required for the increase in [Ca2+]iin NO-treated cells. Thapsigargin induced a rapid cytosolic calcium rise, whereas both a CNG and a nonselective cation channel blocker caused a faster decline in [Ca2+]i, suggesting that capacitive calcium entry contributes to the elevated calcium levels. Antisense inhibition of CNGA2 expression attenuated the NO-induced increases in CNGA2 expression and [Ca2+]iand in capacitive calcium entry. Our results demonstrate that exogenous NO upregulates CNGA2 expression and that this is associated with elevated [Ca2+]iand capacitive calcium entry in porcine PAEC.

Retinal Bipolar Neurons Express the Cyclic Nucleotide-Gated Channel of Cone Photoreceptors

2003 ◽  
Vol 89 (2) ◽  
pp. 754-761 ◽  
Author(s):  
Diane Henry ◽  
Stephanie Burke ◽  
Emiko Shishido ◽  
Gary Matthews
Keyword(s):  
Nitric Oxide ◽  
Single Cell ◽  
Cyclic Nucleotide ◽  
Bipolar Cells ◽  
Cone Photoreceptors ◽  
Nitric Oxide Signaling ◽  
Cng Channel ◽  
Gated Channel ◽  
Goldfish Retina

Cyclic nucleotide-gated (CNG) channels link intracellular cyclic nucleotides to changes in membrane ionic conductance in a variety of physiological contexts. In the retina, in addition to their central role in phototransduction, CNG channels may be involved in nitric oxide signaling in bipolar neurons or in the hyperpolarizing synaptic response to glutamate inon-type (depolarizing) bipolar cells. Despite their potential physiological significance, however, expression of CNG channels has not yet been demonstrated in bipolar cells. To identify CNG channel subtypes in retinal bipolar neurons, we used single-cell molecular biological techniques in morphologically distinctiveon bipolar cells from goldfish retina. Both single-cell in situ hybridization and single-cell RT-PCR demonstrated inon bipolar cells the presence of mRNA for the CNG channel subtype that is also found in cone photoreceptors. Other bipolar cells, which likely represent off cells, did not express the cone CNG channel. Thus the CNG channel of cone photoreceptors is expressed in on bipolar cells, where it may be involved in physiological responses to nitric oxide, or in the sign-inverting glutamatergic synapse that gives rise to the on visual pathway.

Block of cyclic nucleotide-gated channels in salamander olfactory receptor neurons by the guanylyl cyclase inhibitor LY83583

1995 ◽  
Vol 74 (6) ◽  
pp. 2759-2762 ◽  
Author(s):  
T. Leinders-Zufall ◽  
F. Zufall
Keyword(s):  
Guanylyl Cyclase ◽  
Cyclic Nucleotide ◽  
Olfactory Receptor ◽  
Cell Voltage ◽  
Olfactory Receptor Neurons ◽  
Response Curves ◽  
Experimental Conditions ◽  
Activated State ◽  
Cng Channel ◽  
Receptor Neurons

1. Using whole cell voltage-clamp recordings, the guanylyl cyclase inhibitor LY83583 [6-(phenylamino)-5,8-quinolinedione] is shown to act as a potent blocker of cyclic nucleotide-gated (CNG) channels in isolated olfactory receptor neurons (ORNs) of the tiger salamander. 2. Under our experimental conditions, onset of the blockade by LY83583 occurs on the time scale of seconds and is completely reversed upon wash-out of the drug. Dose-response curves reveal a Kd of 1.4 microM (at -60 mV). Other data suggest that LY83583 acts within the CNG channel pore and that the channels must be in an activated state before the drug can exert its effect. 3. It appears that LY83583 can act on both CNG channels and soluble guanylyl cyclase (sGC) and that these two effects can be distinguished by their different recovery behaviors. The LY83583-induced blockade of CNG channels activated directly by guanosine 3',5' cyclic monophosphate (cGMP) is rapidly reversible (with a recovery time constant of approximately 3 s), whereas previous results have shown that no recovery is obtained during minute-long washing periods when the channels are activated indirectly through exogenous carbon monoxide application, which acts as a stimulator of sGC in ORNs. 4. LY83583 appears to be a novel and useful agent in examining neural functions due to CNG channel responses.

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