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Anesth Analg 2000;90:727-732
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

Patch-Clamp Analysis of Anesthetic Interactions with Recombinant SK2 Subtype Neuronal Calcium-Activated Potassium Channels

John C. Dreixler, PhD, Andrew Jenkins, PhD, Ying-Jun Cao, MD, Jeffrey D. Roizen, and Khaled M. Houamed, PhD

Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois

Address correspondence and reprint requests to Dr. Khaled M. Houamed, Department of Anesthesia and Critical Care, The University of Chicago Medical Center, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637. Address e-mail to khouamed{at}midway.uchicago.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Small conductance calcium-activated potassium channels (SK) mediate spike frequency adaptation and underlie the slow afterhyperpolarization in central neurons. We tested the actions of several anesthetics on the SK2 subtype of recombinant SK channels, cloned from rat brain and functionally expressed in a mammalian cell line. Butanol, ethanol, ketamine, lidocaine, and methohexital blocked recombinant SK2 channel currents, measured in the whole-cell patch clamp recording mode. The block was reversible, dose-dependent, and of variable efficacy. The inhaled anesthetics chloroform, desflurane, enflurane, halothane, isoflurane, and sevoflurane produced little or no block when applied at 1 minimum alveolar anesthetic concentration; varying degrees of modulation were observed at very large concentrations (10 minimum alveolar concentration). The extent of block by inhaled anesthetics did not appear to depend on concentration or membrane voltage.

Implications: We describe differential effects of anesthetics on cloned small conductance calcium-activated potassium channels from brain that may play a role in generating the effects or side effects of anesthetics.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Potassium channels of the small conductance subfamily (SK) are characterized by their small unitary conductance, membrane-voltage independent gating, and exquisitely high sensitivity to activation by their natural ligand, intracellular calcium. Neuronal SK channels mediate the phenomenon of spike frequency adaptation, which converts a tonically firing neuron to phasic behavior. Intracellular calcium ([Ca2+]i) accumulates during a train of action potentials, and progressively activates more SK channels. The activated SK channels hyperpolarize the neuron and decrease its input impedance, leading to refractoriness. Once the action potential firing is stopped, a slow afterhyperpolarization (sAHP) ensues, mediated by the still active SK channels. As [Ca2+]i dissipates by extrusion and uptake mechanisms, the SK channel-mediated sAHP decays, and the neuron becomes excitable again.

In addition to [Ca2+]i, neuronal SK channels are also modulated by second messenger systems activated by G protein coupled receptors (GPCRs), such as ß-adrenergic, muscarinic, metabotropic glutamate, and GABAB, as well as receptors for adenosine and dopamine. The inhibition of SK channels in the hippocampus during fight-or-flight situations is thought to be the molecular underpinning of attentiveness (1,2). Generally, in the brain, modulation of SK channels is a major effector mechanism for GPCRs affecting behavior (1,3). Underscoring the important role of SK channels in behavioral phenotype are the effects of apamin injection into the brain. This specific SK channel blocker causes long-term sleep disturbances, hyperexcitability, changes in learning ability, seizures, and neuronal degeneration (4,5). Two reports have also linked defects in these channels with predisposition to schizophrenia, bipolar disorder, and epilepsy (6,7).

Previous studies have shown that various anesthetic drugs interact with sAHP in neuronal preparations (e.g., see Ref. 8). As previously explained, the magnitude and time-course of sAHP are dependent not only on the calcium channel activity and [Ca2+]i metabolism, but also on upstream processes such as receptor, G protein, and kinase activities. The advent of SK channel cloning (9,10) has made possible the study of the direct interaction of these channels with drugs. We investigated the effects of anesthetics and related drugs on the predominant neuronal SK channel subtype, SK2, expressed in a heterologous system.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All experiments were performed at room temperature (20°–25°C) on recombinant rat brain SK2 channels (rSK2) (9), permanently expressed in a cell line derived from HEK 293 cells. SK2 channel cDNA was isolated from a rat brain library and verified by sequencing. The cell line was generated by transfecting the HEK 293 cells with a plasmid encoding the rSK2 sequence and a geneticin-resistance gene contained within the mammalian expression vector pcDNA3.0 (Invitrogen, Carlsbad, CA). Geneticin-resistant colonies were clonally purified, propagated, and tested for rSK2 expression by patch clamp (both whole cell and single channel analysis). The cells were grown in minimal essential medium supplemented with 10% fetal calf serum, antibiotics (penicillin and streptomycin), sodium pyruvate, the glutamine substitute Glutamax (Life Technologies, Rockville, MD) and 1 mg/mL geneticin. The cells were incubated at 37°C in water saturated 5% CO2 atmosphere, and passaged one to two times weekly. The cells were plated on plastic Petri dishes or polylysine coated glass coverslips 1–2 days before the experiments.

The thin-wall borosilicate glass patch pipettes used to measure whole-cell SK2-channel currents had tip resistance of 4–10 M{Omega} when filled with an intracellular solution of the composition, (in mM): K+ methyl sulfate, 137.5; CaCl2, 2; MgCl2, 1; EGTA, 3; HEPES, 10; ATP, 3; and glucose, 5; pH, 7.4. We determined analytically the calcium affinity for the EGTA batch used in this study (11,12). By using this affinity, the calculated free calcium ion concentration [Ca2+] of this solution (approximately 0.8 µM) is sufficient for near maximal activation of the SK2 channels (9,12). The cell under study was constantly perfused with a modified Ringer’s solution [composition, (in mM): NaCl, 117; KCl, 30; CaCl2, 2; MgCl2, 1; HEPES, 10; glucose, 5; NaHCO3, 2; pH, 7.4] by using a rapid microperfusion device. This device consisted of a 500 µm-diameter glass pipette connected, via a 10:1 manifold and valves, to reservoirs containing test solutions. The outlet of the microperfusion device was mounted on a micromanipulator and maneuvered adjacent to the cell under study. The time constant of this system was estimated, from junction potential changes on switching the perfusate from Ringer’s solution to 10% Ringer’s solution, to be approximately 1 s (11). In addition, the recording chamber was constantly perfused with a modified mammalian Ringer’s solution.

A different perfusion setup was used to apply the inhaled anesthetics. This setup was as previously described (13). It consists of an 80-mL perfusion chamber continuously perfused at 25 mL/min. Drugs were rapidly delivered to the cell by local perfusion by using an RSC-100 motor-driven solution exchange device (Biologic, Claix, France). The speed of exchange as measured by dye application was <1 s (13). Anesthetic losses for this system have been measured by using gas chromatography (M. D. Krasowski, unpublished data, 1999) and have been found to be 5%–10% of the applied minimum alveolar anesthetic concentration (MAC). MAC values were taken to be: isoflurane, 370 µM; enflurane, 420 µM; halothane, 290 µM; sevoflurane, 360 µM; and chloroform, 910 µM and are similar to published values (14). There is currently no published concentration for 1 MAC desflurane, however, it is likely to be close to 280 µM (E. I Eger, II, oral communication, September 1999).

The cells were voltage-clamped at -100-mV holding potential; the potassium reversal potential under these conditions was approximately -30 mV. SK2 channel current was observed as a sustained inward current developing rapidly as the interior of the cell equilibrated with the large [Ca2+] pipette solution. To quantify the magnitude of the SK2 current, we applied supramaximal concentration (10 µM) of the specific SK2 channel blocker dequalinium. Brief application of this drug maximally and reversibly blocked the SK2 current (Figure 1). In control experiments (data not shown), nontransfected HEK 293 cells did not express a dequalinium-sensitive current. Furthermore, the nondesensitizing dequalinium-sensitive current was only observed in SK2-expressing cells when they were dialyzed with large [Ca2+] solutions. Additionally, experiments with changing the extracellular potassium concentration indicate that the [Ca2+]i-activated, dequalinium-sensitive current is carried by potassium ions (data not shown). We internally normalized all our block experiments to the block achieved by 10 µM dequalinium in each cell. Normalized block by drugs (mean ± SD) was plotted against drug dose and fitted, by using a least-squares minimization algorithm, with the expression: Go


where I is the inhibition (block), relative to the maximal inhibition (Imax), achieved at drug dose C, KD is the apparent dissociation constant, and n is the Hill number, a measure of the molecularity (stoichiometry and cooperativity) of the reaction; Hill coefficients of greater than one suggest that more than one anesthetic molecule binds to the channel to modulate it.



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  		Figure 1. Block of small conductance calcium-activated potassium channel (SK) by an anesthetic. The figure shows two contiguous segments of membrane current recording of whole-cell clamped HEK 293 cell permanently expressing the SK2 subtype of recombinant rat brain small conductance calcium-activated potassium channels. The cell was clamped at -100 mV; the SK current is inward; the dotted line indicates the zero current level. The block by dequalinium indicates the magnitude of the SK current. Note the dose-dependence and reversibility of the methohexital block.

 

   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In this study, two IV anesthetics, two alcohols, and the local anesthetic lidocaine reversibly and dose-dependently blocked rSK2 channels. Figure 1 illustrates an example of the dose-dependent inhibition of rSK2 channel current by the barbiturate methohexital. Anesthetic block compared with that attained by our control drug, 10 µM dequalinium, was partial. The relative efficacy of anesthetic block is summarized in Figure 2. Figure 3 shows the curve fits of the dose-response data to the equation defined previously; in this case the data are internally normalized to the maximal block attained by each anesthetic. Table 1 lists the variables extracted from the fits of the data in Figure 3.



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  		Figure 2. Maximal block by IV anesthetics. Bar graphs indicate the maximal block, normalized to 10 µM dequalinium block, achieved by the noninhaled anesthetics used in this study; error bars indicate the SEM; numbers in brackets indicate the number of cells.

 


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  		Figure 3. Concentration-dependence of anesthetic block. The block from recordings such as that shown in Figure 1, was normalized internally to the maximal block by the particular drug, and fitted with logistic expression (see text), the values of the fit variables as well as the absolute values of the block are listed in Table 1. The error bars indicate SD. A, Block of channel currents by butanol, ketamine and lidocaine. B, Block of channel currents by ethanol and methohexital.

 

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  		Table 1. Parameters of Dose-Dependent Block by Anesthetic Agents
 
We also observed partial and reversible block of rSK2 channels by the six inhaled anesthetics tested. At 1 MAC, all these anesthetics blocked the rSK2 channels slightly (Figure 4). As compared with block at 1 MAC, the responses at 10 MAC did not appear to be dose-dependent in a straightforward manner; we observed more block with some anesthetics, and diminished block with others (Figure 4). Neither 1 MAC nor 10 MAC of the inhaled anesthetics tested, caused a significant change in SK2 currents (0.2 < P < 0.7; unpaired Student’s t-tests). Current-voltage relations of the dequalinium-sensitive SK2 channel current showed that the observed lack of substantial alteration by inhaled anesthetics persisted at all potentials tested (-100 mV to +60 mV; data not shown).



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  		Figure 4. Inhibition of small conductance calcium-activated potassium channels by inhaled anesthetics. The bar graphs indicate the normalized inhibition (or enhancement) of small conductance channel currents in the presence of 1 MAC (left side bars), or 10 MAC (right). Error bars indicate the SEM; numbers in brackets indicate the number of cells. MAC = minimum alveolar anesthetic concentration.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our study was designed to test SK2 channels—the ion channels that underlie spike frequency adaptation and control interspike interval in mammalian central neurons, and to determine whether they present a target for anesthetics. This is the first study to examine the effects of anesthetic molecules on recombinant SK channels. As stated previously, the activity of native neuronal SK channels integrates [Ca2+]i with various hormone receptor-activated second messenger systems. We were able to examine directly the effects of the anesthetics on the SK channels, thereby bypassing possible interactions with such upstream processes, involved in sAHP generation, such as activation of calcium channels, GPCRs, G proteins, protein kinases, and calcium uptake mechanisms.

Ketamine, a dissociative anesthetic, was the most potent blocker we tested; it blocked up to 70% of recombinant SK2 channel current with an apparent KD of 470 µM. Our data are consistent with data obtained on other native potassium channels (15). Our results suggest that ketamine blocks SK2 channels with equal potency to its block of sodium channels; it is, however, three times more potent at blocking SK2 channels than voltage-gated, delayed rectifier, potassium channels (50% inhibiting concentration [IC50] approximately 900 µM). Other studies have found ketamine a more potent blocker of ATP-gated channels (KD approximately 63 µM) (16), and large conductance calcium- and voltage-gated potassium channels (KD approximately 230 µM) (17). However, in contrast to our study, in both these studies (16,17)) ketamine was applied to the intracellular aspect of the channel. Ketamine blocks N-methyl-D-aspartate receptors at approximately 10 times larger potency than we observed for SK2 channels (18). Moreover, the concentrations for blocking N-methyl-D-aspartate receptors closely overlap with concentrations for clinical anesthesia (10–60 µM) (14). Taken together with previous studies, our data suggests that block of SK channels is unlikely to be the main conduit of ketamine anesthetic action, however, that at clinical concentrations of the drug, there may be a measurable effect on SK channels.

The local anesthetic, lidocaine, blocked approximately 80% of the recombinant SK2 channel current with an apparent KD of 4.44 mM. Brau et al. (19) reported approximately fourfold smaller KD (1.2 mM) for lidocaine block of voltage-gated K channels in peripheral nerve; an uncharacterized, voltage-independent, K channel was much more sensitive to block (KD approximately 220 µM). Kindler et al. (20) reported that lidocaine blocks a recombinant two pore domain potassium channel with similar potency (KD = 222 µM). The transient outward current, KA, was also much more sensitive to lidocaine (IC50 of approximately160 µM) (21). Lidocaine also interferes with intracellular calcium regulation with similar potency to its effect on SK channels (22). Such effects, in vivo, would be expected to indirectly modulate SK channel currents. In contrast to our study and the others cited previously, Sbarbaro et al. (23) showed that the antiarrhythmic effect of lidocaine occurs at plasma concentrations of a few µM, suggesting that block of SK channels is unlikely to occur in a clinical setting.

Our results indicate that large concentrations of ethanol and butanol block recombinant SK2 channels by up to approximately 50%. The apparent KDs for the alcohol block were 74 and 104 mM for ethanol and butanol, respectively. Previous work on sAHPs, which are mediated by native SK channels, yielded contradictory data. Carlen et al. (8), found that ethanol, at the concentrations we used, augmented the SK channel-mediated sAHP in hippocampal neurons. Others report that ethanol generated opposite effects; a depression of the sAHP in hippocampal and cerebellar Purkinje neurons consistent with an SK channel block (24,25). Direct comparison between our study and studies in native neurons, are complicated by the pleiotropic effects of ethanol on cellular signal transduction systems. Ethanol modulates calcium channels and various kinase systems, all of which would be expected to ultimately influence the sAHP waveform (26). In conclusion, our results show, for the first time, that ethanol at quasi-anesthetic concentrations may directly modulate SK channels.

Methohexital blocked roughly 30% of SK2 current with an apparent KD of 0.8 mM. This compares with its block of inward rectifier potassium channels in mast cells (IC50 approximately 0.15 mM) (27). Because barbiturates also block calcium channels (28), it is expected that the block of SK channels and block of calcium channels will combine to produce additive attenuation of neuronal sAHPs.

We also examined the effect of inhaled anesthetics on recombinant SK2 channels. None of the inhaled anesthetics, applied at clinical (1 MAC) or supraclinical (10 MAC) concentrations, altered the magnitude of SK2 currents significantly. In general, however, larger concentrations of inhaled anesthetics depressed the SK channels more, except chloroform, which, interestingly, caused a small potentiation. This effect of chloroform is reminiscent of its action on recombinant Shaker B voltage-gated potassium channels (29). In our study, halothane was without effect, whereas chloroform and isoflurane had opposite effects on the SK potassium channels. In general, our data showing that inhaled anesthetics depress SK channels are in agreement with previous work on other types of potassium channels, including those gated by membrane voltage (29), large conductance, voltage- and calcium-activated (30), and G proteins (31). Most significantly, Scharff and Foder (32) showed that halothane inhibits the Gardos channel in red blood cells; this channel (SK4) has recently been cloned (12) and shown to be similar in sequence and properties to the channel in our study. Moreover, several studies have shown that inhaled anesthetics inhibit voltage-gated calcium channels, which normally would mediate the calcium influx necessary for SK channel activation (e.g., see ref. 33).

In conclusion, we have reported the interactions of anesthetic molecules on recombinant SK channels. Our study, to our knowledge, is the first such study on recombinant SK channels. Our approach follows a recent tradition of investigating drug action at ion channels by using recombinant systems. The obvious strengths of this approach, simplicity and reproducibility, are countered by its limitations, i.e., it is overly reductive. Whereas we studied the effects on a homomeric recombinant channel, its native counterpart may be a heteromer. Furthermore, the membrane microenvironment for the recombinant SK channels in our expression system is likely to be different from that of a myelinated neuron, affecting the phase partitioning of the anesthetics and their apparent affinity. The two functions of SK channels, regulation of electrical excitability in neurons and hormone release in neuroendocrine cells, depend on the interplay between different cellular components, including calcium influx, other modulatory receptors, and protein phosphorylation reactions, as well as membrane voltage. It follows that the effects of anesthetics on these SK channel-mediated cellular events would be the sum of the anesthetic sensitivities of all of the cellular components involved. Our study did not address the molecular mechanisms of SK channel block by anesthetics. Moreover, several SK channel subtypes have now been identified in neurons, smooth muscle, and other tissues. Clearly, it would be desirable to investigate the mechanisms of block and the SK channel-subtype specificity of anesthetic action.


   Acknowledgments
 
Supported by grants from the Brain Research Foundation and the Diabetes Research and Training Center, The University of Chicago, Chicago, IL, and The Whitehall Foundation.

The authors would like to thank Neil Harrison, for support, and L. K. Kaczmarek and W. Joiner (Yale University) for providing materials.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication November 5, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press