scholarly journals Effects of permeating ions and cGMP on gating and conductance of rod-type cyclic nucleotide-gated (CNGA1) channels

2004 ◽  
Vol 560 (3) ◽  
pp. 605-616 ◽  
Author(s):  
Jana Kusch ◽  
Vasilica Nache ◽  
Klaus Benndorf
Keyword(s):  
Cyclic Nucleotide ◽  
Cnga1 Channels

scholarly journals Gating of Cyclic Nucleotide-Gated (CNGA1) Channels by cGMP Jumps and Depolarizing Voltage Steps

2006 ◽  
Vol 90 (9) ◽  
pp. 3146-3154 ◽  
Author(s):  
Vasilica Nache ◽  
Jana Kusch ◽  
Volker Hagen ◽  
Klaus Benndorf
Keyword(s):  
Cyclic Nucleotide ◽  
Cnga1 Channels

scholarly journals Multiple mechanisms underlying rectification in retinal cyclic nucleotide-gated (CNGA1) channels

2013 ◽  
Vol 1 (6) ◽  
pp. e00148 ◽  
Author(s):  
Manuel Arcangeletti ◽  
Arin Marchesi ◽  
Monica Mazzolini ◽  
Vincent Torre
Keyword(s):  
Cyclic Nucleotide ◽  
Cnga1 Channels

scholarly journals Salt Bridges and Gating in the COOH-terminal Region of HCN2 and CNGA1 Channels

2004 ◽  
Vol 124 (6) ◽  
pp. 663-677 ◽  
Author(s):  
Kimberley B. Craven ◽  
William N. Zagotta
Keyword(s):  
Crystal Structure ◽  
Cyclic Nucleotide ◽  
Sequence Similarity ◽  
Terminal Region ◽  
Hcn Channels ◽  
Salt Bridges ◽  
Linker Region ◽  
Channel Opening ◽  
Intersubunit Interactions ◽  
Cnga1 Channels

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels and cyclic nucleotide-gated (CNG) channels are activated by the direct binding of cyclic nucleotides. The intracellular COOH-terminal regions exhibit high sequence similarity in all HCN and CNG channels. This region contains the cyclic nucleotide-binding domain (CNBD) and the C-linker region, which connects the CNBD to the pore. Recently, the structure of the HCN2 COOH-terminal region was solved and shown to contain intersubunit interactions between C-linker regions. To explore the role of these intersubunit interactions in intact channels, we studied two salt bridges in the C-linker region: an intersubunit interaction between C-linkers of neighboring subunits, and an intrasubunit interaction between the C-linker and its CNBD. We show that breaking these salt bridges in both HCN2 and CNGA1 channels through mutation causes an increase in the favorability of channel opening. The wild-type behavior of both HCN2 and CNGA1 channels is rescued by switching the position of the positive and negative residues, thus restoring the salt bridges. These results suggest that the salt bridges seen in the HCN2 COOH-terminal crystal structure are also present in the intact HCN2 channel. Furthermore, the similar effects of the mutations on HCN2 and CNGA1 channels suggest that these salt bridge interactions are also present in the intact CNGA1 channel. As disrupting the interactions leads to channels with more favorable opening transitions, the salt bridges appear to stabilize a closed conformation in both the HCN2 and CNGA1 channels. These results suggest that the HCN2 COOH-terminal crystal structure contains the C-linker regions in the resting configuration even though the CNBD is ligand bound, and channel opening involves a rearrangement of the C-linkers and, thus, disruption of the salt bridges. Discovering that one portion of the COOH terminus, the CNBD, can be in the activated configuration while the other portion, the C-linker, is not activated has lead us to suggest a novel modular gating scheme for HCN and CNG channels.

scholarly journals The analysis of desensitizing CNGA1 channels reveals molecular interactions essential for normal gating

2009 ◽  
Vol 133 (4) ◽  
pp. 375-386 ◽  
Author(s):  
Monica Mazzolini ◽  
Claudio Anselmi ◽  
Vincent Torre
Keyword(s):  
Cyclic Nucleotide ◽  
Double Mutant ◽  
Pore Wall ◽  
Wild Type ◽  
Pore Region ◽  
Mutant Channel ◽  
K Channels ◽  
Outer Vestibule ◽  
Channel Gate ◽  
Cnga1 Channels

The pore region of cyclic nucleotide–gated (CNG) channels acts as the channel gate. Therefore, events occurring in the cyclic nucleotide–binding (CNB) domain must be coupled to the movements of the pore walls. When Glu363 in the pore region, Leu356 and Thr355 in the P helix, and Phe380 in the upper portion of the S6 helix are mutated into an alanine, gating is impaired: mutant channels E363A, L356A, T355A, and F380A desensitize in the presence of a constant cGMP concentration, contrary to what can be observed in wild-type (WT) CNGA1 channels. Similarly to C-type inactivation of K+ channels, desensitization in these mutant channels is associated with rearrangements of residues in the outer vestibule. In the desensitized state, Thr364 residues in different subunits become closer and Pro366 becomes more accessible to extracellular reagents. Desensitization is also observed in the mutant channel L356C, but not in the double-mutant channel L356C+F380C. Mutant channels L356F and F380K did not express, but cGMP-gated currents with a normal gating were observed in the double-mutant channels L356F+F380L and L356D+F380K. Experiments with tandem constructs with L356C, F380C, and L356C+F380C and WT channels indicate that the interaction between Leu356 and Phe380 is within the same subunit. These results show that Leu356 forms a hydrophobic interaction with Phe380, coupling the P helix with S6, whereas Glu363 could interact with Thr355, coupling the pore wall to the P helix. These interactions are essential for normal gating and underlie the transduction between the CNB domain and the pore.

Ticlopidine and Clopidogrel (SR 25990C) Selectively Neutralize ADP Inhibition of PGE1-Activated Platelet Adenylate Cyclase in Rats and Rabbits

1991 ◽  
Vol 65 (02) ◽  
pp. 186-190 ◽  
Author(s):  
G Defreyn ◽  
C Gachet ◽  
P Savi ◽  
F Driot ◽  
J P Cazenave ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Adenylate Cyclase ◽  
Direct Effect ◽  
Cyclic Nucleotide ◽  
Camp Accumulation ◽  
Rabbit Platelets ◽  
Camp Levels ◽  
Kinetics Of ◽  
Camp Elevation ◽  
Rat Platelets

SummaryTiclopidine and its potent analogue, clopidogrel, are powerful inhibitors of ADP-induced platelet aggregation. In order to improve the understanding of this ADP-selectivity, we studied the effect of these compounds on PGE1-stimulated adenylate cyclase and on the inhibition of this enzyme by ADP, epinephrine and thrombin. Neither drug changed the basal cAMP levels nor the kinetics of cAMP accumulation upon PGEj-stimulation in rat or rabbit platelets, which excludes any direct effect on adenylate cyclase or on cyclic nucleotide phosphodiesterase. However, the drop in cAMP levels observed after addition of ADP to PGEr stimulated control platelets was inhibited in platelets from treated animals. In contrast, the drop in cAMP levels produced by epinephrine was not prevented by either drug in rabbit platelets. In rat platelets, thrombin inhibited the PGEX-induced cAMP elevation but this effect seems to be entirely mediated by the released ADP. Under these conditions, it was not surprising to find that clopidogrel also potently inhibited that effect of thrombin on platelet adenylate cyclase. In conclusion, ticlopidine and clopidogrel selectively neutralize the ADP inhibition of PGEr activated platelet adenylate cyclase in rats and rabbits.

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