scholarly journals Inherited macular degeneration-associated mutations in CNGB3 increase the ligand sensitivity and spontaneous open probability of cone cyclic nucleotide-gated channels

2015 ◽  
Vol 6 ◽  
Author(s):  
Peter C. Meighan ◽  
Changhong Peng ◽  
Michael D. Varnum
Keyword(s):  
Macular Degeneration ◽  
Cyclic Nucleotide ◽  
Open Probability ◽  
Cyclic Nucleotide Gated Channels ◽  
Ligand Sensitivity

scholarly journals Phosphorylation of Mammalian Olfactory Cyclic Nucleotide-Gated Channels Increases Ligand Sensitivity

1998 ◽  
Vol 18 (1) ◽  
pp. 164-173 ◽  
Author(s):  
Frank Müller ◽  
Wolfgang Bönigk ◽  
Federico Sesti ◽  
Stephan Frings
Keyword(s):  
Cyclic Nucleotide ◽  
Cyclic Nucleotide Gated Channels ◽  
Ligand Sensitivity

scholarly journals Matrix metalloproteinase-9 and -2 enhance the ligand sensitivity of photoreceptor cyclic nucleotide-gated channels

Channels ◽  
2012 ◽  
Vol 6 (3) ◽  
pp. 181-196 ◽  
Author(s):  
Peter C. Meighan ◽  
Starla E. Meighan ◽  
Elizabeth D. Rich ◽  
R. Lane Brown ◽  
Michael D. Varnum
Keyword(s):  
Matrix Metalloproteinase ◽  
Cyclic Nucleotide ◽  
Matrix Metalloproteinase 9 ◽  
Cyclic Nucleotide Gated Channels ◽  
Metalloproteinase 9 ◽  
Ligand Sensitivity

scholarly journals Effects of Ultraviolet Modification on the Gating Energetics of Cyclic Nucleotide–Gated Channels

2000 ◽  
Vol 116 (2) ◽  
pp. 253-282 ◽  
Author(s):  
Thomas R. Middendorf ◽  
Richard W. Aldrich
Keyword(s):  
Cyclic Nucleotide ◽  
Channel Gating ◽  
Quantum Yields ◽  
Open Probability ◽  
Current Increase ◽  
Cyclic Nucleotide Gated Channels ◽  
Channel Opening ◽  
High Concentrations ◽  
Current Reduction ◽  
Opposing Effects

Middendorf et al. (Middendorf, T.R., R.W. Aldrich, and D.A. Baylor. 2000. J. Gen. Physiol. 116:227–252) showed that ultraviolet light decreases the current through cloned cyclic nucleotide–gated channels from bovine retina activated by high concentrations of cGMP. Here we probe the mechanism of the current reduction. The channels' open probability before irradiation, Po(0), determined the sign of the change in current amplitude that occurred upon irradiation. UV always decreased the current through channels with high initial open probabilities [Po(0) > 0.3]. Manipulations that promoted channel opening antagonized the current reduction by UV. In contrast, UV always increased the current through channels with low initial open probabilities [Po(0) ≤ 0.02], and the magnitude of the current increase varied inversely with Po(0). The dual effects of UV on channel currents and the correlation of both effects with Po(0) suggest that the channels contain two distinct classes of UV target residues whose photochemical modification exerts opposing effects on channel gating. We present a simple model based on this idea that accounts quantitatively for the UV effects on the currents and provides estimates for the photochemical quantum yields and free energy costs of modifying the UV targets. Simulations indicate that UV modification may be used to produce and quantify large changes in channel gating energetics in regimes where the associated changes in open probability are not measurable by existing techniques.

scholarly journals Ligand-binding domain subregions contributing to bimodal agonism in cyclic nucleotide–gated channels

2011 ◽  
Vol 137 (6) ◽  
pp. 591-603 ◽  
Author(s):  
Wai-Fung Wong ◽  
Kerry S.C. Chan ◽  
Matthew S. Michaleski ◽  
Adam Haesler ◽  
Edgar C. Young
Keyword(s):  
Steady State ◽  
Ligand Binding ◽  
Cyclic Nucleotide ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Phosphate Binding ◽  
Open Probability ◽  
Cyclic Nucleotide Gated Channels ◽  
Functional Features ◽  
Apparent Attenuation

Cyclic nucleotide–gated (CNG) channels bind cGMP or cAMP in a cytoplasmic ligand–binding domain (BD), and this binding typically increases channel open probability (Po) without inducing desensitization. However, the catfish CNGA2 (fCNGA2) subtype exhibits bimodal agonism, whereby steady-state Po increases with initial cGMP-binding events (“pro” action) up to a maximum of 0.4, but decreases with subsequent cGMP-binding events (“con” action) occurring at concentrations >3 mM. We sought to clarify if low pro-action efficacy was either necessary or sufficient for con action to operate. To find BD residues responsible for con action or low pro-action efficacy or both, we constructed chimeric CNG channels: subregions of the fCNGA2 BD were substituted with corresponding sequence from the rat CNGA4 BD, which does not support con action. Constructs were expressed in frog oocytes and tested by patch clamp of cell-free membranes. For nearly all BD elements, we found at least one construct where replacing that element preserved robust con action, with a ratio of steady-state conductances, g(10 mM cGMP)/g(3 mM cGMP) < 0.75. When all of the BD sequence C terminal of strand β6 was replaced, g(10 mM cGMP)/g(3 mM cGMP) was increased to 0.95 ± 0.05 (n = 7). However, this apparent attenuation of con action could be explained by an increase in the efficacy of pro action for all agonists, controlled by a conserved “phosphate-binding cassette” motif that contacts ligand; this produces high Po values that are less sensitive to shifts in gating equilibrium. In contrast, substituting a single valine in the N-terminal helix αA abolished con action (g(30 mM cGMP)/g(3 mM cGMP) increased to 1.26 ± 0.24; n = 7) without large increases in pro-action efficacy. Our work dissociates the two functional features of low pro-action efficacy and con action, and moreover identifies a separate structural determinant for each.

scholarly journals Influence of Permeant Ions on Gating in Cyclic Nucleotide–gated Channels

2002 ◽  
Vol 121 (1) ◽  
pp. 61-72 ◽  
Author(s):  
Miguel Holmgren
Keyword(s):  
Cyclic Nucleotide ◽  
Single Channel ◽  
Hek293 Cells ◽  
Monovalent Cations ◽  
Open Probability ◽  
Cyclic Nucleotide Gated Channels ◽  
Open Conformation ◽  
Open Time ◽  
Main Effect ◽  
The Stability

Cyclic nucleotide–gated channels are key components in the transduction of visual and olfactory signals where their role is to respond to changes in the intracellular concentration of cyclic nucleotides. Although these channels poorly select between physiologically relevant monovalent cations, the gating by cyclic nucleotide is different in the presence of Na+ or K+ ions. This property was investigated using rod cyclic nucleotide–gated channels formed by expressing the subunit 1 (or α) in HEK293 cells. In the presence of K+ as the permeant ion, the affinity for cGMP is higher than the affinity measured in the presence of Na+. At the single channel level, subsaturating concentrations of cGMP show that the main effect of the permeant K+ ions is to prolong the time channels remain open without major changes in the shut time distribution. In addition, the maximal open probability was higher when K+ was the permeant ion (0.99 for K+ vs. 0.95 for Na+) due to an increase in the apparent mean open time. Similarly, in the presence of saturating concentrations of cAMP, known to bind but unable to efficiently open the channel, permeant K+ ions also prolong the time channels visit the open state. Together, these results suggest that permeant ions alter the stability of the open conformation by influencing of the O→C transition.

scholarly journals C-Linker of Cyclic Nucleotide–gated Channels Controls Coupling of Ligand Binding to Channel Gating

1999 ◽  
Vol 113 (1) ◽  
pp. 17-34 ◽  
Author(s):  
Pierre Paoletti ◽  
Edgar C. Young ◽  
Steven A. Siegelbaum
Keyword(s):  
Amino Acids ◽  
Ligand Binding ◽  
Cyclic Nucleotide ◽  
Transmembrane Domain ◽  
Open Probability ◽  
C Elegans ◽  
Cyclic Nucleotide Gated Channels ◽  
Ligand Gating ◽  
Conserved Amino Acids ◽  
Precise Role

Cyclic nucleotide–gated channels are composed of a core transmembrane domain, structurally homologous to the voltage-gated K+ channels, and a cytoplasmic ligand-binding domain. These two modules are joined by ∼90 conserved amino acids, the C-linker, whose precise role in the mechanism of channel activation by cyclic nucleotides is poorly understood. We examined cyclic nucleotide–gated channels from bovine photoreceptors and Caenorhabditis elegans sensory neurons that show marked differences in cyclic nucleotide efficacy and sensitivity. By constructing chimeras from these two channels, we identified a region of 30 amino acids in the C-linker (the L2 region) as an important determinant of activation properties. An increase in both the efficacy of gating and apparent affinity for cGMP and cAMP can be conferred onto the photoreceptor channel by the replacement of its L2 region with that of the C. elegans channel. Three residues within this region largely account for this effect. Despite the profound effect of the C-linker region on ligand gating, the identity of the C-linker does not affect the spontaneous, ligand-independent open probability. Based on a cyclic allosteric model of activation, we propose that the C-linker couples the opening reaction in the transmembrane core region to the enhancement of the affinity of the open channel for agonist, which underlies ligand gating.

scholarly journals Presence of functional hyperpolarisation-activated cyclic nucleotide-gated channels in clonal alpha cell lines and rat islet alpha cells

Diabetologia ◽  
2008 ◽  
Vol 51 (12) ◽  
pp. 2290-2298 ◽  
Author(s):  
Y. Zhang ◽  
N. Zhang ◽  
A. V. Gyulkhandanyan ◽  
E. Xu ◽  
H. Y. Gaisano ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cyclic Nucleotide ◽  
Alpha Cell ◽  
Alpha Cells ◽  
Cyclic Nucleotide Gated Channels
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