Protein kinase C co‐expression and the effects of halothane on rat skeletal muscle sodium channels

Mounsey, J. Paul; Patel, Manoj K.; Mistry, Dilaawar J.; John, J. Edward; Moorman, J. Randall

doi:10.1038/sj.bjp.0702877

Cited by 9 publications

(12 citation statements)

References 42 publications

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“…Thus, sodium channels pass this test of anesthetic relevance. Studies of volatile anesthetic action on cloned sodium channels show somewhat divergent results that, in part, may be due to differences in the origin (neural versus nonneural origin of the channel) (148,158,159).…”

Section: -Htmentioning

confidence: 97%

Inhaled Anesthetics and Immobility: Mechanisms, Mysteries, and Minimum Alveolar Anesthetic Concentration

Sonner¹,

Antognini

Dutton

et al. 2003

Anesthesia & Analgesia

276

186

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Studies using molecular modeling, genetic engineering, neurophysiology/pharmacology, and whole animals have advanced our understanding of where and how inhaled anesthetics act to produce immobility (minimum alveolar anesthetic concentration; MAC) by actions on the spinal cord. Numerous ligand- and voltage-gated channels might plausibly mediate MAC, and specific amino acid sites in certain receptors present likely candidates for mediation. However, in vivo studies to date suggest that several channels or receptors may not be mediators (e.g., gamma-aminobutyric acid A, acetylcholine, potassium, 5-hydroxytryptamine-3, opioids, and alpha(2)-adrenergic), whereas other receptors/channels (e.g., glycine, N-methyl-D-aspartate, and sodium) remain credible candidates.

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Section: -Htmentioning

confidence: 97%

Inhaled Anesthetics and Immobility: Mechanisms, Mysteries, and Minimum Alveolar Anesthetic Concentration

Sonner¹,

Antognini

Dutton

et al. 2003

Anesthesia & Analgesia

276

186

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“…Human Na v 1.4 heterologously expressed in Xenopus oocytes is inhibited by isoflurane and halothane,10 whereas rat Na v 1.4 in the same expression system was reported to be insensitive to halothane unless co-expressed with protein kinase C (PKC) 24. Our results indicate that rat Na v 1.4 expressed in a mammalian cell line is inhibited by multiple inhaled anesthetics in the absence of over-expression or pharmacological activation of PKC indicating that PKC activation is apparently not required for inhibition.…”

Section: Discussionmentioning

confidence: 99%

Comparative Effects of Halogenated Inhaled Anesthetics on Voltage-gated Na+Channel Function

Ouyang¹,

Herold

Hemmings

2009

Anesthesiology

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Background Inhibition of voltage-gated Na+ channels (Nav) is implicated in the synaptic actions of volatile anesthetics. We studied the effects of the major halogenated inhaled anesthetics (halothane, isoflurane, sevoflurane, enflurane and desflurane) on Nav1.4, a well characterized pharmacological model for Nav effects. Methods Na+ currents (INa) from rat Nav1.4 α-subunits heterologously expressed in Chinese hamster ovary cells were analyzed by whole cell voltage-clamp electrophysiological recording. Results Halogenated inhaled anesthetics reversibly inhibited Nav1.4 in a concentration- and voltage-dependent manner at clinical concentrations. At equi-anesthetic concentrations, peak INa was inhibited with a rank order of desflurane > halothane ≈ enflurane > isoflurane ≈ sevoflurane from a physiological holding potential (−80 mV). This suggests that the contribution of Na+ channel block to anesthesia might vary in an agent-specific manner. From a hyperpolarized holding potential that minimizes inactivation (−120 mV), peak INa was inhibited with a rank order of potency for tonic inhibition of peak INa of halothane > isoflurane ≈ sevoflurane > enflurane > desflurane. Desflurane produced the largest negative shift in voltage-dependence of fast inactivation consistent with its more prominent voltage-dependent effects. A comparison between isoflurane and halothane showed that halothane produced greater facilitation of current decay, slowing of recovery from fast inactivation, and use-dependent block than isoflurane. Conclusions Five halogenated inhaled anesthetics all inhibit a voltage-gated Na+ channel by voltage- and use-dependent mechanisms. Agent-specific differences in efficacy for Na+ channel inhibition due to differential state-dependent mechanisms creates pharmacologic diversity that could underlie subtle differences in anesthetic and nonanesthetic actions.

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“…This inactivation gate phosphorylation site is significant in the response of Na channels to halothane. We have previously shown that the enhancement of Na current decay induced by halothane in oocytes co‐expressing Na channels and PKC was absent in a Na channel mutant lacking this phosphorylation site ( Mounsey et al ., 1999 ). In the experiments reported here the mechanism of this effect was found to be a decrease in the amplitude of the slow phase of Na current decay, which resulted in a reduction of charge movement, and hence suppression of Na current.…”

Section: Discussionmentioning

confidence: 99%

“…Our methods for isolation and mRNA injection of Xenopus laevis oocytes have been described ( Mounsey et al ., 1995 ; 1999 ). Oocytes were defolliculated manually the day of the electrophysiologic experiments, 2–5 days after injection.…”

Section: Methodsmentioning

confidence: 99%

“…This effect was dependent on the phosphorylation site in the Na channel inactivation gate known to be a PKC substrate. Halothane also caused a small reduction in Na current amplitude, which was independent of phosphorylation of this inactivation gate site ( Mounsey et al ., 1999 ). In view of the experiments of Bosnjak and co‐workers, we set out to assess whether PKC sensitized cardiac and neuronal Na channel α‐subunits to halothane in our preparation.…”

Section: Introductionmentioning

confidence: 99%

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Sodium channel isoform‐specific effects of halothane: protein kinase C co‐expression and slow inactivation gating

Patel

Mistry

John

et al. 2000

British J Pharmacology

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1 The modulatory eect of protein kinase C (PKC) on the response of Xenopus oocyte-expressed Na channel a-subunits to halothane (2-bromo-2-chloro-1,1,1-tri¯uroethane) was studied. Na currents through rat skeletal muscle, rat brain and human cardiac muscle Na channels were assessed using cell-attached patch clamp recordings. PKC activity was increased by co-expression of a constitutively active PKC a-isozyme. 2 Decay of macroscopic Na currents could be separated into fast and slow exponential phases. 3 PKC co-expression alone slowed Na current decay in neuronal channels, through enhancement of the amplitude of the slower phase of decay. 4 Halothane (1.0 mM) was without eect on any of the three isoforms expressed alone but, after co-expression of PKC, there was enhancement of Na current decay with reduction in charge movement through skeletal muscle and neuronal channels. Cardiac channels were relatively insensitive to halothane. 5 Enhanced Na current decay resulted from suppression of the slow phase, without eect on the faster phase or on either decay t. 6 Suppression of Na current through skeletal muscle channels was concentration-dependent over the therapeutic range and was described by third order reaction kinetics, with an IC 50 of 0.55 mM. 7 We conclude that the halothane suppresses skeletal muscle and brain Na channel activity in this preparation through a reduction in the slow mode of inactivation gating, but only after PKC coexpression. Cardiac Na channels were relatively insensitive to halothane. The mechanism is likely to involve phosphorylation of the channel inactivation gate, although phosphorylation of other sites in the channel may account for the isoform speci®c dierences.

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Protein kinase C co‐expression and the effects of halothane on rat skeletal muscle sodium channels

Cited by 9 publications

References 42 publications

Inhaled Anesthetics and Immobility: Mechanisms, Mysteries, and Minimum Alveolar Anesthetic Concentration

Inhaled Anesthetics and Immobility: Mechanisms, Mysteries, and Minimum Alveolar Anesthetic Concentration

Comparative Effects of Halogenated Inhaled Anesthetics on Voltage-gated Na+Channel Function

Sodium channel isoform‐specific effects of halothane: protein kinase C co‐expression and slow inactivation gating

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