Inhibitory Effects of Ketamine and Halothane on Recombinant Potassium Channels from Mammalian Brain

Kulkarni, Rama S.; Zorn, Lynda; Anantharam, Vellareddy; Bayley, Hagan; Treistman, Steven N.

doi:10.1097/00000542-199604000-00018

Cited by 27 publications

(7 citation statements)

References 29 publications

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“…Inhibition of voltage-gated K ϩ currents by general anesthetics has been reported previously (Kulkarni et al, 1996;Friederich and Urban, 1999). Isoflurane hyperpolarizes rat vascular smooth muscle, which is attributed in part to enhanced opening of Ca 2ϩ -activated and ATP-sensitive K ϩ channels, but not voltage-gated or inward rectifier K ϩ channels (Kokita et al, 1999).…”

Section: Isoflurane Depresses Nerve Terminal Action Potentials 805mentioning

confidence: 85%

Depression by Isoflurane of the Action Potential and Underlying Voltage-Gated Ion Currents in Isolated Rat Neurohypophysial Nerve Terminals

Ouyang

Hemmings

2004

J Pharmacol Exp Ther

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We characterized the effects of the volatile anesthetic isoflurane on the ion currents that contribute to the action potential (AP) in isolated rat neurohypophysial (NHP) nerve terminals using patch-clamp electrophysiology. Mean resting membrane potential and AP amplitude were Ϫ62.3 Ϯ 4.1 and 69.2 Ϯ 2.9 mV, respectively, in NHP terminals. Two components of outward K ϩ current (I K ) were identified in voltage-clamp recordings: a transient I K and a sustained I K with minimal inactivation. Some terminals displayed a slowly activating I K , probably the big Ca 2ϩ -activated K ϩ current (BK). Isoflurane reversibly inhibited AP amplitude and increased AP half-width in normal extracellular Ca 2ϩ (2.2 mM). In high extracellular Ca 2ϩ (10 mM), isoflurane also reduced the afterhypolarization peak amplitude. A transient tetrodotoxin-sensitive Na ϩ current (I Na ) was the principal current mediating the depolarizing phase of the AP. A slowly inactivating Cd 2ϩ -sensitive current (probably a voltagegated Ca 2ϩ current; I Ca ) followed the initial I Na . Isoflurane reversibly inhibited both I Na and I Ca elicited by a voltage-stimulus based on an averaged AP waveform. The isoflurane IC 50 for AP waveform-evoked I Na was 0.36 mM. Isoflurane (0.84 Ϯ 0.04 mM) inhibited AP waveform-evoked I Ca by 37.5 Ϯ 0.16% (p Ͻ 0.05). The isoflurane IC 50 for peak I K was 0.83 mM and for sustained I K was 0.73 mM, with no effect on the voltage dependence of activation. The results indicate that multiple voltage-gated ion channels (Na ϩ Ͼ K ϩ Ͼ Ca 2ϩ ) in NHP terminals, although not typical central nervous system terminals, are inhibited by the volatile general anesthetic isoflurane. The net inhibitory effects of volatile anesthetics on nerve terminal action potentials and excitability result from integrated actions on multiple voltage-gated currents.

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Section: Isoflurane Depresses Nerve Terminal Action Potentials 805mentioning

confidence: 85%

Depression by Isoflurane of the Action Potential and Underlying Voltage-Gated Ion Currents in Isolated Rat Neurohypophysial Nerve Terminals

Ouyang

Hemmings

2004

J Pharmacol Exp Ther

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“…78 The presence of C-type inactivation is critical for the block of a variety of K ϩ channels by the general anesthetics ketamine and halothane. 79 Thus, the interactions between drug binding and C-type inactivation are of widespread importance for many clinically relevant situations.…”

Section: The Role Of C-type Inactivation In Drugmentioning

confidence: 99%

Inactivation of Voltage-Gated Cardiac K ⁺ Channels

Rasmusson

Morales

Wang

et al. 1998

Circulation Research

133

126

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Abstract-Inactivation is the process by which an open channel enters a stable nonconducting conformation after a depolarizing change in membrane potential. Inactivation is a widespread property of many different types of voltage-gated ion channels. Recent advances in the molecular biology of K ϩ channels have elucidated two mechanistically distinct types of inactivation, N-type and C-type. N-type inactivation involves occlusion of the intracellular mouth of the pore through binding of a short segment of residues at the extreme N-terminal. In contrast to this "tethered ball" mechanism of N-type inactivation, C-type inactivation involves movement of conserved core domain residues that result in closure of the external mouth of the pore. Although C-type inactivation can show rapid kinetics that approach those observed for N-type inactivation, it is often thought of as a slowly developing and slowly recovering process. Current models of C-type inactivation also suggest that this process involves a relatively localized change in conformation of residues near the external mouth of the permeation pathway. The rate of C-type inactivation and recovery can be strongly influenced by other factors, such as N-type inactivation, drug binding, and changes in [K ϩ ] o . These interactions make C-type inactivation an important biophysical process in determining such physiologically important properties as refractoriness and drug binding. C-type inactivation is currently viewed as arising from small-scale rearrangements at the external mouth of the pore. This review will examine the multiplicity of interactions of C-type inactivation with N-terminal-mediated inactivation and drug binding that suggest that our current view of C-type inactivation is incomplete. This review will suggest that C-type inactivation must involve larger-scale movements of transmembrane-spanning domains and that such movements contribute to the diversity of kinetic properties observed for C-type inactivation. (Circ Res. 1998;82:739-750.)

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“…The large amplitude of the Kv2‐mediated current in pyramidal neurons suggests important functional roles for these channels. Kv2.1 channels are highly regulated by phosphorylation (Misonou et al 2005 a ; Park et al 2008) and have been implicated in cellular responses to seizures and ischaemia (Misonou et al 2004,2005 b ; Mohapatra et al 2009), mechanisms for intrinsic plasticity (Surmeier and Foehring, 2004; Nataraj et al 2010) and cell death (Pal et al 2003), and responsiveness to anaesthetic agents (Kulkarni et al 1996). There have been relatively few studies of the roles of Kv2 channels in regulating neuronal electrical behaviour, however.…”

Section: Introductionmentioning

confidence: 99%

Kv2 channels regulate firing rate in pyramidal neurons from rat sensorimotor cortex

Guan

Armstrong

Foehring

2013

The Journal of Physiology

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Key points• Neurons express many types of potassium channels that are activated by voltage but relatively little is known concerning the division of labour between different channel types in a given cell.• Our understanding of the functional roles of Kv2 channels has been hindered by the lack of selective pharmacological agents for these channels.• We manipulated Kv2 channel expression by transfecting pyramidal neurons with wild-type and pore mutant channels.• We found that reduction in functional Kv2 channels led to slower firing rates, reduced gain of firing and increased spike frequency adaptation.• We hypothesize that Kv2 channels regulate firing by controlling membrane potential during the inter-spike interval, which in turn regulates availability of voltage-gated sodium channels. AbstractThe largest outward potassium current in the soma of neocortical pyramidal neurons is due to channels containing Kv2.1 α subunits. These channels have been implicated in cellular responses to seizures and ischaemia, mechanisms for intrinsic plasticity and cell death, and responsiveness to anaesthetic agents. Despite their abundance, knowledge of the function of these delayed rectifier channels has been limited by the lack of specific pharmacological agents. To test for functional roles of Kv2 channels in pyramidal cells from somatosensory or motor cortex of rats (layers 2/3 or 5), we transfected cortical neurons with DNA for a Kv2.1 pore mutant (Kv2.1W365C/Y380T: Kv2.1 DN) in an organotypic culture model to manipulate channel expression. Slices were obtained from rats at postnatal days (P7-P14) and maintained in organotypic culture. We used biolistic methods to transfect neurons with gold 'bullets' coated with DNA for the Kv2.1 DN and green fluorescent protein (GFP), GFP alone, or wild type (WT) Kv2.1 plus GFP. Cells that fluoresced green, contained a bullet and responded to positive or negative pressure from the recording pipette were considered to be transfected cells. In each slice, we recorded from a transfected cell and a control non-transfected cell from the same layer and area. Whole-cell voltage-clamp recordings obtained after 3-7 days in culture showed that cells transfected with the Kv2.1 DN had a significant reduction in outward current (∼45% decrease in the total current density measured 200 ms after onset of a voltage step from -78 to -2 mV). Transfection with GFP alone did not affect current amplitude and overexpression of the Kv2.1 WT resulted in greatly increased currents. Current-clamp experiments were used to assess the functional consequences of manipulation of Kv2.1 expression. The results suggest roles for Kv2 channels in controlling membrane potential during the interspike interval (ISI), firing rate, spike frequency adaptation (SFA) and the steady-state gain of firing. Specifically, firing rate and gain were reduced in the Kv2.1 DN cells. The most parsimonious explanation for the effects on firing is that in the absence of Kv2 channels, the membrane remains depolarized during the

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Inhibitory Effects of Ketamine and Halothane on Recombinant Potassium Channels from Mammalian Brain

Cited by 27 publications

References 29 publications

Depression by Isoflurane of the Action Potential and Underlying Voltage-Gated Ion Currents in Isolated Rat Neurohypophysial Nerve Terminals

Depression by Isoflurane of the Action Potential and Underlying Voltage-Gated Ion Currents in Isolated Rat Neurohypophysial Nerve Terminals

Inactivation of Voltage-Gated Cardiac K ⁺ Channels

Kv2 channels regulate firing rate in pyramidal neurons from rat sensorimotor cortex

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Inhibitory Effects of Ketamine and Halothane on Recombinant Potassium Channels from Mammalian Brain

Cited by 27 publications

References 29 publications

Depression by Isoflurane of the Action Potential and Underlying Voltage-Gated Ion Currents in Isolated Rat Neurohypophysial Nerve Terminals

Depression by Isoflurane of the Action Potential and Underlying Voltage-Gated Ion Currents in Isolated Rat Neurohypophysial Nerve Terminals

Inactivation of Voltage-Gated Cardiac K + Channels

Kv2 channels regulate firing rate in pyramidal neurons from rat sensorimotor cortex

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Inactivation of Voltage-Gated Cardiac K ⁺ Channels