Dataset Information

Novel activation of voltage-gated K(+) channels by sevoflurane.

ABSTRACT:

Background

Halogenated inhaled anesthetics modulate voltage-gated ion channels by unknown mechanisms.

Results

Biophysical analyses revealed novel activation of K(v) channels by the inhaled anesthetic sevoflurane.

Conclusion

K(v) channel activation by sevoflurane results from the positive allosteric modulation of activation gating.

Significance

The unique activation of K(v) channels by sevoflurane demonstrates novel anesthetic specificity and offers new insights into allosteric modulation of channel gating. Voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, but the underlying molecular mechanisms are not understood. Alkanols and halogenated inhaled anesthetics such as halothane and isoflurane inhibit the archetypical voltage-gated Kv3 channel homolog K-Shaw2 by stabilizing the resting/closed states. By contrast, sevoflurane, a more heavily fluorinated ether commonly used in general anesthesia, specifically activates K-Shaw2 currents at relevant concentrations (0.05-1 mM) in a rapid and reversible manner. The concentration dependence of this modulation is consistent with the presence of high and low affinity interactions (K(D) = 0.06 and 4 mM, respectively). Sevoflurane (<1 mM) induces a negative shift in the conductance-voltage relation and increases the maximum conductance. Furthermore, suggesting possible roles in general anesthesia, mammalian Kv1.2 and Kv1.5 channels display similar changes. Quantitative description of the observations by an economical allosteric model indicates that sevoflurane binding favors activation gating and eliminates an unstable inactivated state outside the activation pathway. This study casts light on the mechanism of the novel sevoflurane-dependent activation of Kv channels, which helps explain how closely related inhaled anesthetics achieve specific actions and suggests strategies to develop novel Kv channel activators.

SUBMITTER: Barber AF

PROVIDER: S-EPMC3504757 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel activation of voltage-gated K(+) channels by sevoflurane.

Barber Annika F AF Liang Qiansheng Q Covarrubias Manuel M

The Journal of biological chemistry 20121004 48

<h4>Background</h4>Halogenated inhaled anesthetics modulate voltage-gated ion channels by unknown mechanisms.<h4>Results</h4>Biophysical analyses revealed novel activation of K(v) channels by the inhaled anesthetic sevoflurane.<h4>Conclusion</h4>K(v) channel activation by sevoflurane results from the positive allosteric modulation of activation gating.<h4>Significance</h4>The unique activation of K(v) channels by sevoflurane demonstrates novel anesthetic specificity and offers new insights into ...[more]

PMID: 23038249

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Project description:Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na+ channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations (2-10 µM). In both Navs, propofol induced a hyperpolarizing shift of the pre-pulse inactivation curve without any significant effects on recovery from inactivation at strongly hyperpolarized voltages, demonstrating that propofol does not stabilize the inactivated state. Moreover, there was no evidence of fast or slow pore block by propofol in a non-inactivating NaChBac mutant (T220A). Propofol also induced hyperpolarizing shifts of the conductance-voltage relationships with negligible effects on the time constants of deactivation at hyperpolarized voltages, indicating that propofol does not stabilize the open state. Instead, propofol decreases the time constants of macroscopic activation and inactivation. Adopting a kinetic scheme of Nav gating that assumes preferential closed-state recovery from inactivation, a 1.7-fold acceleration of the rate constant of activation and a 1.4-fold acceleration of the rate constant of inactivation were sufficient to reproduce experimental observations with computer simulations. In addition, molecular dynamics simulations and molecular docking suggest that propofol binding involves interactions with gating machinery in the S4-S5 linker and external pore regions. Our findings show that propofol is primarily a positive gating modulator of prokaryotic Navs, which ultimately inhibits the channels by promoting activation-coupled inactivation.

Dataset Information

Novel activation of voltage-gated K(+) channels by sevoflurane.

Background

Results

Conclusion

Significance

Publications

Novel activation of voltage-gated K(+) channels by sevoflurane.

Similar Datasets

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