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Contributions of intracellular ions to kv channel voltage sensor dynamics.

Goodchild SJ, Fedida D - Front Pharmacol (2012)

Bottom Line: However, several other factors not directly linked to the voltage-dependent movement of charged residues within the voltage sensor impact the dynamics of the voltage sensor, such as inactivation, ionic conductance, intracellular ion identity, and block of the channel by intracellular ligands.There is a significant amount of variability in the reported kinetics of voltage sensor deactivation kinetics of Kv channels attributed to different mechanisms such as open state stabilization, immobilization, and relaxation processes of the voltage sensor.These considerations are of critical importance in understanding the molecular determinants of the complete channel gating cycle from activation to deactivation.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia Vancouver, BC, Canada.

ABSTRACT
Voltage-sensing domains (VSDs) of Kv channels control ionic conductance through coupling of the movement of charged residues in the S4 segment to conformational changes at the cytoplasmic region of the pore domain, that allow K(+) ions to flow. Conformational transitions within the VSD are induced by changes in the applied voltage across the membrane field. However, several other factors not directly linked to the voltage-dependent movement of charged residues within the voltage sensor impact the dynamics of the voltage sensor, such as inactivation, ionic conductance, intracellular ion identity, and block of the channel by intracellular ligands. The effect of intracellular ions on voltage sensor dynamics is of importance in the interpretation of gating current measurements and the physiology of pore/voltage sensor coupling. There is a significant amount of variability in the reported kinetics of voltage sensor deactivation kinetics of Kv channels attributed to different mechanisms such as open state stabilization, immobilization, and relaxation processes of the voltage sensor. Here we separate these factors and focus on the causal role that intracellular ions can play in allosterically modulating the dynamics of Kv voltage sensor deactivation kinetics. These considerations are of critical importance in understanding the molecular determinants of the complete channel gating cycle from activation to deactivation.

No MeSH data available.


State model summarizing the effects of intracellular ions on voltage sensor dynamics. The model is described in the text.
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Figure 3: State model summarizing the effects of intracellular ions on voltage sensor dynamics. The model is described in the text.

Mentions: The various pathways affected by intracellular ions have been summarized by the simplified state scheme shown in Figure 3. The scheme assigns the majority of the charge carrying transitions of all the four subunits voltage sensors to the transition between R (resting) and A (activated). Depolarization causes the voltage sensors to shift from R to A, a transition which accounts for the gating charge measured on activation. After activation the pore domain opens sequentially and must shut before the reverse transition from A to R representing charge recovery. Slowing the transition from O to A will have the effect of slowing charge return. After opening, ions may enter the pore and occupy a site (O:IonS1) that prevents closure of the pore and will have the knock-on effect of slowing deactivation kinetics and, if slower than the A to R transition, the rate of charge return will also be slower. The rate of slowing of charge return is subject to modulation of the stability of O:IonS1, which is dependent upon the proximity of other ions and the intrinsic affinity for the pore cavity that the specific ion may have which will be dependent upon size, charge, and solvation. Once opened, or bound with an ion at S1, the channel might also enter an inactivated state (I) associated with a conformational rearrangement that stabilizes the voltage sensor and causes immobilization. The rate of entry into this inactivated state may be impaired by intracellular ions occupying a site that antagonizes inactivation (O:IonS2) – probably through a mechanism similar to the “foot in the door” attenuation of inactivation described for conducting channels (Baukrowitz and Yellen, 1995, 1996). The off rate for each ion site are modified by the multipliers α and β where α ( β, which results in occupancy of S2 impairing the entry into the inactivated state without affecting the return of charge significantly. Alternatively, the entry into the inactivated state could be accelerated by reducing binding at the “foot in the door” site S2 through the depletion of appropriate binding ions by non-permeant cations which favor site S1; an experimental condition necessary to record gating currents from conducting channels which would increase the degree of immobilization observed.


Contributions of intracellular ions to kv channel voltage sensor dynamics.

Goodchild SJ, Fedida D - Front Pharmacol (2012)

State model summarizing the effects of intracellular ions on voltage sensor dynamics. The model is described in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376422&req=5

Figure 3: State model summarizing the effects of intracellular ions on voltage sensor dynamics. The model is described in the text.
Mentions: The various pathways affected by intracellular ions have been summarized by the simplified state scheme shown in Figure 3. The scheme assigns the majority of the charge carrying transitions of all the four subunits voltage sensors to the transition between R (resting) and A (activated). Depolarization causes the voltage sensors to shift from R to A, a transition which accounts for the gating charge measured on activation. After activation the pore domain opens sequentially and must shut before the reverse transition from A to R representing charge recovery. Slowing the transition from O to A will have the effect of slowing charge return. After opening, ions may enter the pore and occupy a site (O:IonS1) that prevents closure of the pore and will have the knock-on effect of slowing deactivation kinetics and, if slower than the A to R transition, the rate of charge return will also be slower. The rate of slowing of charge return is subject to modulation of the stability of O:IonS1, which is dependent upon the proximity of other ions and the intrinsic affinity for the pore cavity that the specific ion may have which will be dependent upon size, charge, and solvation. Once opened, or bound with an ion at S1, the channel might also enter an inactivated state (I) associated with a conformational rearrangement that stabilizes the voltage sensor and causes immobilization. The rate of entry into this inactivated state may be impaired by intracellular ions occupying a site that antagonizes inactivation (O:IonS2) – probably through a mechanism similar to the “foot in the door” attenuation of inactivation described for conducting channels (Baukrowitz and Yellen, 1995, 1996). The off rate for each ion site are modified by the multipliers α and β where α ( β, which results in occupancy of S2 impairing the entry into the inactivated state without affecting the return of charge significantly. Alternatively, the entry into the inactivated state could be accelerated by reducing binding at the “foot in the door” site S2 through the depletion of appropriate binding ions by non-permeant cations which favor site S1; an experimental condition necessary to record gating currents from conducting channels which would increase the degree of immobilization observed.

Bottom Line: However, several other factors not directly linked to the voltage-dependent movement of charged residues within the voltage sensor impact the dynamics of the voltage sensor, such as inactivation, ionic conductance, intracellular ion identity, and block of the channel by intracellular ligands.There is a significant amount of variability in the reported kinetics of voltage sensor deactivation kinetics of Kv channels attributed to different mechanisms such as open state stabilization, immobilization, and relaxation processes of the voltage sensor.These considerations are of critical importance in understanding the molecular determinants of the complete channel gating cycle from activation to deactivation.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia Vancouver, BC, Canada.

ABSTRACT
Voltage-sensing domains (VSDs) of Kv channels control ionic conductance through coupling of the movement of charged residues in the S4 segment to conformational changes at the cytoplasmic region of the pore domain, that allow K(+) ions to flow. Conformational transitions within the VSD are induced by changes in the applied voltage across the membrane field. However, several other factors not directly linked to the voltage-dependent movement of charged residues within the voltage sensor impact the dynamics of the voltage sensor, such as inactivation, ionic conductance, intracellular ion identity, and block of the channel by intracellular ligands. The effect of intracellular ions on voltage sensor dynamics is of importance in the interpretation of gating current measurements and the physiology of pore/voltage sensor coupling. There is a significant amount of variability in the reported kinetics of voltage sensor deactivation kinetics of Kv channels attributed to different mechanisms such as open state stabilization, immobilization, and relaxation processes of the voltage sensor. Here we separate these factors and focus on the causal role that intracellular ions can play in allosterically modulating the dynamics of Kv voltage sensor deactivation kinetics. These considerations are of critical importance in understanding the molecular determinants of the complete channel gating cycle from activation to deactivation.

No MeSH data available.