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Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides.

DeBerg HA, Brzovic PS, Flynn GE, Zagotta WN, Stoll S - J. Biol. Chem. (2015)

Bottom Line: Binding of cyclic nucleotides increases the rate and extent of channel activation and shifts it to less hyperpolarized voltages.We probed the allosteric mechanism of different cyclic nucleotides on the CNBD and on channel gating.We explain these results with a model where different allosteric mechanisms in the CNBD all converge to have the same effect on the C-linker and render all three cyclic nucleotides similarly potent activators of the channel.

View Article: PubMed Central - PubMed

Affiliation: From the Departments of Chemistry, Physiology and Biophysics, and.

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Models for HCN2 gating.A, three-state model for HCN2 gating with separate voltage-dependent activation and opening transitions. The channel can exist in a closed resting state (CR), a closed activated state (CA), and an open state (O). K is the equilibrium constant for voltage activation, L is the equilibrium constant for pore opening. B, modular gating scheme for HCN2. The three modules correspond to equilibria between two states each. The CNBD can be unbound (U) or bound (B) to a cyclic nucleotide ligand, the C-linker can be in a resting (R) or activated (A) state, and the pore can be closed (C) or open (O). The double-head horizontal arrows represent the coupling between the modules.
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Figure 7: Models for HCN2 gating.A, three-state model for HCN2 gating with separate voltage-dependent activation and opening transitions. The channel can exist in a closed resting state (CR), a closed activated state (CA), and an open state (O). K is the equilibrium constant for voltage activation, L is the equilibrium constant for pore opening. B, modular gating scheme for HCN2. The three modules correspond to equilibria between two states each. The CNBD can be unbound (U) or bound (B) to a cyclic nucleotide ligand, the C-linker can be in a resting (R) or activated (A) state, and the pore can be closed (C) or open (O). The double-head horizontal arrows represent the coupling between the modules.

Mentions: We can also estimate ΔΔGintact for the intact channel from our electrophysiology data using a simple three-state model shown in Fig. 7A. This model assumes two sequential transitions, a voltage-dependent transition (associated with the movement of the voltage sensor) and a voltage-independent opening transition that is affected by the binding of cyclic nucleotide. The equilibrium constant for activation of the voltage sensor is K = K0e−V/s and depends on the applied voltage V and the slope factor, s. K, and therefore K0 and s, are assumed independent of the presence and the identity of a cNMP agonist. The equilibrium constant for channel opening, L, depends on the cyclic nucleotide species that is bound. The open probability Po is given by the following equation.


Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides.

DeBerg HA, Brzovic PS, Flynn GE, Zagotta WN, Stoll S - J. Biol. Chem. (2015)

Models for HCN2 gating.A, three-state model for HCN2 gating with separate voltage-dependent activation and opening transitions. The channel can exist in a closed resting state (CR), a closed activated state (CA), and an open state (O). K is the equilibrium constant for voltage activation, L is the equilibrium constant for pore opening. B, modular gating scheme for HCN2. The three modules correspond to equilibria between two states each. The CNBD can be unbound (U) or bound (B) to a cyclic nucleotide ligand, the C-linker can be in a resting (R) or activated (A) state, and the pore can be closed (C) or open (O). The double-head horizontal arrows represent the coupling between the modules.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697172&req=5

Figure 7: Models for HCN2 gating.A, three-state model for HCN2 gating with separate voltage-dependent activation and opening transitions. The channel can exist in a closed resting state (CR), a closed activated state (CA), and an open state (O). K is the equilibrium constant for voltage activation, L is the equilibrium constant for pore opening. B, modular gating scheme for HCN2. The three modules correspond to equilibria between two states each. The CNBD can be unbound (U) or bound (B) to a cyclic nucleotide ligand, the C-linker can be in a resting (R) or activated (A) state, and the pore can be closed (C) or open (O). The double-head horizontal arrows represent the coupling between the modules.
Mentions: We can also estimate ΔΔGintact for the intact channel from our electrophysiology data using a simple three-state model shown in Fig. 7A. This model assumes two sequential transitions, a voltage-dependent transition (associated with the movement of the voltage sensor) and a voltage-independent opening transition that is affected by the binding of cyclic nucleotide. The equilibrium constant for activation of the voltage sensor is K = K0e−V/s and depends on the applied voltage V and the slope factor, s. K, and therefore K0 and s, are assumed independent of the presence and the identity of a cNMP agonist. The equilibrium constant for channel opening, L, depends on the cyclic nucleotide species that is bound. The open probability Po is given by the following equation.

Bottom Line: Binding of cyclic nucleotides increases the rate and extent of channel activation and shifts it to less hyperpolarized voltages.We probed the allosteric mechanism of different cyclic nucleotides on the CNBD and on channel gating.We explain these results with a model where different allosteric mechanisms in the CNBD all converge to have the same effect on the C-linker and render all three cyclic nucleotides similarly potent activators of the channel.

View Article: PubMed Central - PubMed

Affiliation: From the Departments of Chemistry, Physiology and Biophysics, and.

Show MeSH