Novel Activation of Voltage-gated K+ Channels by Sevoflurane

Barber, Annika F.; Liang, Qiansheng; Covarrubias, Manuel

doi:10.1074/jbc.m112.405787

Cited by 35 publications

(59 citation statements)

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“…AziSEVO photolabeling of the b 3 -subunit, b 3 -M1 259 W241 and b 3 -M2 29 A249, again supports this a+/b2 interfacial binding cavity. By using mutagenesis and electrophysiology, other investigators have suggested that SEVO and ISO iso have different binding sites in a variety of potassium channels (22,26,49,50), and our results confirm that this is also true in GABA A receptors. Although comparatively less than ISO, a decrease in SEVO-positive modulation was observed within in vitro studies using a 1 -M2 159 S270W or S270I GABA A receptor mutants (8).…”

Section: Discussionsupporting

confidence: 88%

“…All spectra are provided in Supplemental Figs. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Photolabeled residues and their locations within either receptor are displayed in Table 2.…”

Section: Results a 1 B 3 G 2l Gaba A Receptor Electrophysiology With mentioning

confidence: 99%

“…All animal care and experimental procedures that involved X. laevis frogs were carried out according to a protocol approved by the Institutional Animal Care and Use Committee of Thomas Jefferson University. GABA A receptor currents were recorded as previously reported (21,22). In brief, GABA A receptor wholeoocyte currents were recorded at room temperature (21-23°C) under 2-electrode voltage clamp conditions (OC-725C; Warner Instruments, Hamden, CT, USA).…”

Section: Methodsmentioning

confidence: 99%

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Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors

Woll¹,

Zhou

Bhanu³

et al. 2018

FASEB j.

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Most general anesthetics enhance GABA type A (GABA) receptor activity at clinically relevant concentrations. Sites of action of volatile anesthetics on the GABA receptor remain unknown, whereas sites of action of many intravenous anesthetics have been identified in GABA receptors by using photolabeling. Here, we used photoactivatable analogs of isoflurane (AziISO) and sevoflurane (AziSEVO) to locate their sites on αβγ and αβ GABA receptors. As with isoflurane and sevoflurane, AziISO and AziSEVO enhanced the currents elicited by GABA. AziISO and AziSEVO each labeled 10 residues in αβ receptors and 9 and 8 residues, respectively, in αβγ receptors. Photolabeled residues were concentrated in transmembrane domains and located in either subunit interfaces or in the interface between the extracellular domain and the transmembrane domain. The majority of these transmembrane residues were protected from photolabeling with the addition of excess parent anesthetic, which indicated specificity. Binding sites were primarily located within α+/β- and β+/α- subunit interfaces, but residues in the α+/γ- interface were also identified, which provided a basis for differential receptor subtype sensitivity. Isoflurane and sevoflurane did not always share binding sites, which suggests an unexpected degree of selectivity.-Woll, K. A., Zhou, X., Bhanu, N. V., Garcia, B. A., Covarrubias, M., Miller, K. W., Eckenhoff, R. G. Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors.

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Section: Discussionsupporting

confidence: 88%

Section: Results a 1 B 3 G 2l Gaba A Receptor Electrophysiology With mentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors

Woll¹,

Zhou

Bhanu³

et al. 2018

FASEB j.

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“…A previous study has demonstrated that sevoflurane at 1 mM modestly increases the maximal conductance of hKv1.5 channels and shifts the voltage dependence of activation toward more hyperpolarized potentials, through mechanisms involving a positive allosteric modulation of channel gating (Barber et al, 2012). In contrast, propofol blocks the hKv1.5 current with an IC 50 of 49.3 M (Fig.…”

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confidence: 94%

Interaction of propofol with voltage-gated human Kv1.5 channel through specific amino acids within the pore region

Kojima

Ito

Ding

et al. 2015

European Journal of Pharmacology

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“…Pipette solution contained (in mM): 15 NaCl, 80 CsF, 40 CsCl, 10 EGTA, and 10 Hepes, pH 7.3 adjusted with CsOH. Sevoflurane containing external solution was prepared by sonication and delivered by a gastight perfusion system as previously described (52). To eliminate inaccuracies caused by membrane lipid retention of anesthetic molecules, each cell was exposed to only one dose of anesthetic agent and washout data were not used.…”

Section: Methodsmentioning

confidence: 99%

Modulation of a voltage-gated Na⁺channel by sevoflurane involves multiple sites and distinct mechanisms

Barber

Carnevale

Klein

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Halogenated inhaled general anesthetic agents modulate voltagegated ion channels, but the underlying molecular mechanisms are not understood. Many general anesthetic agents regulate voltagegated Na + (Na V ) channels, including the commonly used drug sevoflurane. Here, we investigated the putative binding sites and molecular mechanisms of sevoflurane action on the bacterial Na V channel NaChBac by using a combination of molecular dynamics simulation, electrophysiology, and kinetic analysis. Structural modeling revealed multiple sevoflurane interaction sites possibly associated with NaChBac modulation. Electrophysiologically, sevoflurane favors activation and inactivation at low concentrations (0.2 mM), and additionally accelerates current decay at high concentrations (2 mM). Explaining these observations, kinetic modeling suggests concurrent destabilization of closed states and low-affinity open channel block. We propose that the multiple effects of sevoflurane on NaChBac result from simultaneous interactions at multiple sites with distinct affinities. This multiple-site, multiple-mode hypothesis offers a framework to study the structural basis of general anesthetic action.anesthesia | MD simulations | anesthetics | membrane proteins G eneral anesthetic agents have been in use for more than 160 y.However, we still understand relatively little about their mechanisms of action, which greatly limits our ability to design safer and more effective general anesthetic agents. Ion channels of the central nervous system are known to be key targets of general anesthetic agents, as their modulation can account for the endpoints and side effects of general anesthesia (1-4). Many families of ion channels are modulated by general anesthetic agents, including ligand-gated, voltage-gated, and nongated ion channels (2, 5-7). Mammalian voltage-gated Na + (Na V ) channels, which mediate the upstroke of the action potential, are regulated by numerous inhaled general anesthetic agents (8-14), which generally cause inhibition. Previous work showed that inhaled general anesthetic agents, including sevoflurane, isoflurane, desflurane, and halothane, mediate inhibition by increasing the rate of Na + channel inactivation, hyperpolarizing steady-state inactivation, and slowing recovery from inactivation (11,(15)(16)(17)(18). Inhibition of presynaptic Na V channels in the spinal cord is proposed to lead to inhibition of neurotransmitter release, facilitating immobilization-one of the endpoints of general anesthesia (14,19,20). Despite the importance of Na V channels as general anesthetic targets, little is known about interaction sites or the mechanisms of action.What is known about anesthetic sites in Na V channels comes primarily from the local anesthetic field. Local anesthetic agent binding to Na V channels is well characterized. These amphiphilic drugs enter the channel pore from the intracellular side, causing open-channel block (21). Investigating molecular mechanisms of mammalian Na V channel modulation by general anesthetic agents...

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Novel Activation of Voltage-gated K+ Channels by Sevoflurane

Cited by 35 publications

References 42 publications

Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors

Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors

Interaction of propofol with voltage-gated human Kv1.5 channel through specific amino acids within the pore region

Modulation of a voltage-gated Na⁺channel by sevoflurane involves multiple sites and distinct mechanisms

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Novel Activation of Voltage-gated K+ Channels by Sevoflurane

Cited by 35 publications

References 42 publications

Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors

Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors

Interaction of propofol with voltage-gated human Kv1.5 channel through specific amino acids within the pore region

Modulation of a voltage-gated Na+channel by sevoflurane involves multiple sites and distinct mechanisms

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Modulation of a voltage-gated Na⁺channel by sevoflurane involves multiple sites and distinct mechanisms