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Anesth Analg 2003;96:112-118
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Modulation of GABAA Receptor Function by Nonhalogenated Alkane Anesthetics: The Effects on Agonist Enhancement, Direct Activation, and Inhibition

Douglas E. Raines, MD*{dagger}, Robert J. Claycomb, BS{dagger}, and Stuart A. Forman*{dagger}

*Department of Anesthesia, Harvard Medical School; and {dagger}Department of Anesthesia, Massachusetts General Hospital, Boston

Address correspondence and reprint requests to D.E. Raines, MD, Department of Anesthesia, Massachusetts General Hospital, 32 Fruit St., Boston, MA 02114. Address e-mail to DRaines{at}partners.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
At clinically relevant concentrations, ethers, alcohols, and halogenated alkanes enhance agonist action on the {gamma}-aminobutyric acidA (GABAA) receptor, whereas nonhalogenated alkanes do not. Many anesthetics also directly activate and/or inhibit GABAA receptors, actions that may produce important behavioral effects; although, the effects of nonhalogenated alkane anesthetics on GABAA receptor direct activation and inhibition have not been studied. In this study, we assessed the abilities of two representative nonhalogenated alkanes, cyclopropane and butane, to enhance agonist action, directly activate, and inhibit currents mediated by expressed {alpha}1ß2{gamma}2L GABAA receptors using electrophysiological techniques. Our studies reveal that cyclopro- pane and butane enhance agonist action on the GABAA receptor at concentrations that exceed those required to produce anesthesia. Neither nonhalogenated alkane directly activated nor inhibited GABAA receptors, even at concentrations that approach their aqueous saturated solubilities. These results strongly suggest that the behavioral actions of nonhalogenated alkane anesthetics do not result from their abilities to enhance agonist actions, directly activate, or inhibit {alpha}1ß2{gamma}2L GABAA receptors and are consistent with the hypothesis that electrostatic interactions between anesthetics and their protein binding sites modulate GABAA receptor potency.

IMPLICATIONS: When normalized to either their in vivo anesthetic potencies or hydrophobicities, cyclopropane and butane are 1–1.5 orders of magnitude less potent enhancers of agonist action on {alpha}1ß2{gamma}2L GABAA receptors than isoflurane. Additionally, cyclopropane and butane fail to directly activate or inhibit receptors, even at near aqueous saturating concentrations. Thus, it is unlikely that either enhancement or inhibition of the most common GABAA receptor subtype in the brain accounts for the behavioral activities of cyclopropane and butane.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The {gamma}-aminobutyric acidA (GABAA) receptor is one member of a superfamily of anesthetic-sensitive ligand-gated ion channels that also includes the nicotinic acetylcholine receptor, the glycine receptor, and the 5-hydroxytryptamine3 receptor (1,2). It is widely distributed throughout the central nervous system where it is the major inhibitory neurotransmitter receptor. Although more than one dozen GABAA receptor subunits have been identified, it is believed that the most common GABAA receptors in mammalian brains are composed of {alpha}1, ß2, and {gamma}2 subunits in a stoichiometry of 2:2:1 (3–5).

General anesthetics can alter the function of the GABAA receptor in three distinct ways. First, anesthetics can enhance the actions of agonist (6–8). This is evident in single-cell or patch-clamp electrophysiological studies as an increase in GABAergic current elicited by small concentrations of agonist (9–11). In studies using a range of agonist concentrations, this action reflects a reduction in the GABAA receptor’s agonist 50% effective concentration (EC50) (12–15). Second, anesthetics can directly open GABAA receptor channels even in the absence of agonist, an action termed direct activation (16). Finally, anesthetics can inhibit GABAergic currents elicited by large concentrations of the agonist (6,11,17–19).

In a previous study (20), we demonstrated that, unlike nearly all other general anesthetics, the nonhalogenated alkanes cyclopropane and butane fail to enhance the actions of agonist on the major GABAA receptor subtype at a pharmacologically relevant concentration (1.6 minimum alveolar anesthetic concentration [MAC]). We hypothesized that this inactivity reflected low potency because of the inability of nonhalogenated alkanes to engage in electrostatic (e.g., hydrogen bonding and/or dipolar) interactions with protein targets. In the present study, we tested this hypothesis by using a range of anesthetic concentrations including those that approached aqueous saturation. In addition, we evaluated the abilities of these nonhalogenated alkane anesthetics to directly activate and inhibit GABAA receptors, anesthetic actions that may have important behavioral consequences.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Complimentary DNAs for the human {alpha}1ß2{gamma}2L GABAA receptors subunits were gifts from Paul J. Whiting, PhD, (Merck, Sharp, & Dohme Research Laboratories, Essex, United Kingdom). Messenger RNAs were synthesized in vitro from linearized complimentary DNA using commercial kits (Ambion, Austin, TX), isolated using affinity beads (BIO-101, Vista, CA), and stored at -80°C.

Oocytes were surgically removed from ice-cold tricaine anesthetized Xenopus laevis frogs and incubated in 1.0 mg/mL of collagenase dissolved in OR-2 solution (82 mM of NaCl, 2 mM of KCl, 1 mM of MgCl2, and 5 mM of HEPES; pH value of 7.6) until the follicular membrane was removed. Healthy, mature oocytes were injected with a total of ~60 ng of messenger RNA coding for the {alpha}1, ß2, and {gamma}2L subunits of the human GABAA receptor subunits in a 2:2:1 (wt/wt) ratio. After injection, oocytes were transferred to a filter-sterilized ND-96 solution (96 mM of NaCl, 2 mM of KCl, 1 mM of CaCl2, 0.8 mM of MgCl2, and 5 mM of HEPES; pH value of 7.6) containing 5 U/mL of penicillin and 5 µg/mL of streptomycin and incubated at 17°C for at least 24 h to promote expression.

Oocytes were impaled with 2 glass electrodes filled with 3 M of KCl with resistances of 0.2–2 M{Omega}, voltage clamped at -50 mV by a GeneClamp 500B amplifier (Axon Instruments, Foster City, CA), and perfused with ND-96 buffer at 4–6 mL/min. The perfusion system was constructed of glass and Teflon to minimize evaporative and adsorptive loss of drug and controlled by a six-channel valve controller (Warner Instruments, Hamden, CT) interfaced with an Axon Digidata card and driven by a personal computer using pClamp 8.0 by Axon Instruments. Each anesthetic-containing solution was prepared by diluting a saturated solution within a gas-tight glass syringe that was then attached to the perfusion system. Gas chromatographic studies demonstrated that loss of drug during dilution and transit through the perfusion system was <15%. All experiments were performed at room temperature (20°C–22°C). The aqueous saturated solubilities of isoflurane, cyclopropane, and butane are 15 mM, 10.6 mM, and 1.1 mM, respectively (21). The aqueous concentration corresponding to the human MACs of cyclopropane, butane, and isoflurane were taken as 820 µM, 160 µM, and 280 µM, respectively (21).

Agonist Enhancement
Before anesthetic studies, the concentration of GABA that produces ~5% of the maximal current response (EC5 GABA) was determined for each oocyte expressing GABAA receptors by measuring peak currents induced by a range of GABA concentrations in ND-96 buffer. To assess the effect of anesthetic on currents elicited by EC5 GABA, a control peak current was first elicited by perfusing each oocyte with ND-96 buffer containing EC5 GABA for 50 s. After a 5-min recovery period, the effect of the anesthetic was assessed by co-applying anesthetic along with EC5 GABA for 50 s. After another 5-min recovery period, reversibility was confirmed by repeating the control experiment. The control peak current response was quantified as the average of the two control currents. The effect of anesthetic on the GABAA receptor’s GABA EC50 was determined by measuring currents elicited by a range of GABA concentrations (1–1000 µM) in the absence or presence of the anesthetic.

Direct Activation
Oocytes expressing GABAA receptors were perfused first with the ND-96 buffer alone for 30 s, then with a buffer-containing anesthetic (no GABA) for 50 s, and then with the buffer alone again. The anesthetic-elicited current was quantified as the peak current recorded during anesthetic exposure. To construct anesthetic concentration-response curves for direct activation, the anesthetic-elicited response was normalized to that elicited by 1 mM of GABA in the same oocyte.

Inhibition
Oocytes expressing GABAA receptors were perfused first with the ND-96 buffer containing 1 mM of GABA for 15 s and then pulsed with the buffer containing 1 mM of GABA plus anesthetic for 40 s. Inhibition was quantified as the reduction in current mea-sured at the end of the anesthetic pulse.

Each data point represents the mean of at least three measurements obtained using different oocytes, and the error bars indicate the SD from the mean. Data points on GABA concentration-response curves were fit to a Hill equation in the form (Equation 1):

equation


where Inorm is the current normalized to that elicited by 1 mM of GABA, EC50 is the concentration of GABA that elicits 50% of the maximal current, and n is the Hill coefficient.

Data points on anesthetic concentration-response curves for inhibition were fit to a Hill equation in the form (Equation 2:)

equation


where Inorm is the fraction of current that is inhibited by isoflurane, IC50 is the concentration of isoflurane that inhibits 50% of the current, and n is the Hill coefficient.

The reported errors for all fitted variables are the SDs derived from the curve fit.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1A shows representative current traces obtained upon perfusing oocytes expressing {alpha}1ß2{gamma}2L GABAA receptors with EC5 GABA alone (control) or with 1 MAC of cyclopropane or butane. For comparison, the current enhancement induced by 1 MAC of isoflurane is also shown in this figure using the same oocyte. Cyclopropane and butane had little or no effect on currents elicited by EC5 GABA at concentrations equivalent to 1 MAC. In contrast, isoflurane increased the current by 520%. At large concentrations, cyclopropane and butane did significantly and reversibly increase the GABA-elicited currents (Fig. 1B). Studies using a wide range of anesthetic concentrations revealed that all three anesthetics enhanced the current induced by EC5 GABA in a concentration-dependent manner (Fig. 1C). Although isoflurane’s enhancing action began to plateau at concentrations more than 2 MAC, the effects of cyclopropane and butane failed to plateau, even at concentrations that exceeded 90% of their aqueous saturated solubilities. Because the actions of these two anesthetics failed to reach a maximum, it was not possible to reliably determine anesthetic EC50s. Instead, the potency of each anesthetic was quantified as the concentration required to double the control current. This value was determined from a linear fit of a plot of the normalized current versus anesthetic concentration. Because isoflurane’s enhancing action began to plateau at large concentrations, data obtained in the presence of isoflurane concentrations larger than 2 MAC were not included in the fit. Table 1 lists the results of this analysis along with each anesthetic’s oil/aqueous partition coefficient.



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  		Figure 1. The effect of cyclopropane, butane, and isoflurane on {gamma}-aminobutyric acidA (GABAA) receptor currents elicited by 5% effective concentration (EC5) GABA. (A) Representative current traces obtained in the presence of 1 minimum alveolar anesthetic concentration (MAC) of cyclopropane, 1 MAC of butane, or 1 MAC of isoflurane. Control currents before and after anesthetic exposure are also shown. (B) Representative current traces obtained in the presence of 6 MAC of cyclopropane or 6 MAC of butane. Control currents before and after anesthetic exposure are also shown. (C) Anesthetic concentration-response curves for current enhancement by cyclopropane, butane, and isoflurane on a double logarithmic axis. The symbols represent the mean of at least three measurements obtained in three different oocytes, and the error bars indicate the SD for each data point. The solid curves represent the results of a linear fit of each data set. Each anesthetic’s relative potency was quantified as the concentration required to double the control current (dashed lines).

 

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  		Table 1. Agonist Enhancing Potencies and Oil/Aqueous Partition Coefficients of Cyclopropane, Butane, and Isoflurane
 
Previous studies (12–15) have shown that anesthetics such as isoflurane, halothane, and ethanol enhance the effects of small concentrations of GABA on GABAA receptors by reducing the receptor’s EC50 for GABA (increasing the receptor’s apparent affinity for GABA). To determine whether the agonist enhancement produced by large alkane concentrations also reflects an anesthetic-induced reduction in the GABAA receptor’s EC50 for GABA, we measured the GABAA receptor’s EC50 for GABA in the absence or presence of large concentrations of cyclopropane and butane (Fig. 2). In the absence of anesthetic, the GABAA receptor’s EC50 for GABA was 25 ± 1 µM. In the presence of 12.2 MAC of cyclopropane or 6.3 MAC of butane, the EC50 was reduced to 14 ± 1 µM or 16 ± 2 µM, respectively.



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  		Figure 2. The effect of 12.2 minimum alveolar anesthetic concentration (MAC) of cyclopropane or 6.3 MAC of butane on {gamma}-aminobutyric acidA (GABAA) receptor’s 50% effective concentration (EC50) for GABA. A fit of each data set to Equation 1 indicated that cyclopropane and butane reduced the GABAA receptor’s EC50 for GABA from 25 ± 1 µM to 14 ± 1 µM and 16 ± 2 µM, respectively. The symbols represent the mean of at least three measurements obtained in three different oocytes, and the error bars indicate the SD for each data point.

 
Figures 3, A and B, show representative current traces obtained when oocytes expressing {alpha}1ß2{gamma}2L GABAA receptors were perfused with either cyclopropane or butane. Direct activation by isoflurane is also shown in these figures for comparison. Cyclopropane and butane elicited essentially no current response at either 1 MAC or even at 6 MAC, whereas isoflurane induced relatively large currents at both concentrations. Figure 3C plots the current elicited by anesthetic (normalized to that elicited by 1 mM of GABA in the same oocyte) as a function of anesthetic concentration and demonstrates that at all concentrations studied, cyclopropane and butane induced little response. In contrast, isoflurane elicited currents in a concentration-dependent manner before reaching a maximum at 6 MAC. This maximum current response was 25% ± 1% of that response elicited by 1 mM of GABA.



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  		Figure 3. The direct activating actions of cyclopropane, butane, and isoflurane on {gamma}-aminobutyric acidA (GABAA) receptors. (A) Representative current traces induced by 1 minimum alveolar anesthetic concentration (MAC) of cyclopropane, 1 MAC of butane, or 1 MAC of isoflurane. (B) Representative current traces induced by approximately 6 MAC of cyclopropane, butane, or isoflurane. For oocytes shown in A and B, 1 mM of GABA elicited currents ranging from 3–6 µA (data not shown). (C) Anesthetic concentration-response curves for direct activation by cyclopropane, butane, and isoflurane. Currents were normalized to that elicited by 1 mM of GABA in the same oocyte. The symbols represent the mean of at least three measurements obtained in three different oocytes, and the error bars indicate the SD for each data point.

 
Perfusion of oocytes expressing {alpha}1ß2{gamma}2L GABAA receptors with the buffer containing 1 mM of GABA resulted in a peak current response followed by an approximately monoexponential current decay reflecting the process of desensitization (Fig. 4A). Pulsing oocytes with near aqueous saturating concentrations of cyclopropane or butane during activation by 1 mM of GABA had no detectable inhibitory effect on GABAA receptor currents (Fig. 4, B and C); current traces were essentially indistinguishable from those obtained in experiments in which oocytes were not exposed to anesthetic (Fig. 4A). Figure 4D demonstrates that pulsing oocytes with isoflurane resulted in a rapid, reversible reduction in measured current. Currents did not completely recover upon termination of isoflurane application presumably because desensitization continued during the isoflurane pulse. Figure 4E shows the effects of a wide range of anesthetic concentrations on currents elicited by 1 mM of GABA. Isoflurane significantly inhibited GABAergic currents at a concentration as small as 3 MAC. Its IC50, determined by fitting the isoflurane data set to Equation 2, was 6.5 ± 0.4 MAC (1.8 ± 0.1 mM), and the Hill coefficient for this effect was 2.0 ± 0.2. No IC50s were determined for cyclopropane and butane because they produced no detectable inhibition at any concentration.



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  		Figure 4. The {gamma}-aminobutyric acidA (GABAA) receptor inhibitory actions of cyclopropane, butane, and isoflurane. (A) Representative current trace obtained upon perfusing an oocyte with 1 mM of GABA. The dotted line is an exponential fit of the current decay (desensitization) that occurs upon prolonged agonist exposure. (B and C) Representative current trace obtained upon perfusing an oocyte with 1 mM of GABA for 15 s and then applying of pulse of either 12.2 MAC of cyclopropane (B) or 6.3 MAC of butane (C) for 40 s. (D) Representative current trace obtained upon perfusing an oocyte with 1 mM of GABA and then applying a pulse of 10 MAC of isoflurane for 40 s. The dotted line is an exponential fit of the current decay that occurred before and after the anesthetic pulse and was used to estimate the uninhibited current. The double-arrow line indicates the current inhibited by the isoflurane pulse. (E) Anesthetic concentration-response curves for current inhibition by cyclopropane, butane, and isoflurane. The half-maximal inhibitory concentration (IC50) for isoflurane was 6.5 ± 0.4 MAC (1.8 ± 0.1 mM), and the Hill coefficient was 2.0 ± 0.2. No IC50s were determined for cyclopropane or butane because they failed to inhibit at any concentration. The symbols represent the mean of at least three measurements obtained in three different oocytes, and the error bars indicate the SD for each data point.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
At concentrations sufficient to produce anesthesia, general anesthetics representing a wide range of chemical classes including alcohols, ethers, halogenated alkanes, and barbiturates enhance the function of the major inhibitory neurotransmitter receptor in the central nervous system, the GABAA receptor (6–14,16,22). Specifically, these general anesthetics enhance the action of small concentrations of agonist on GABAA receptors and directly activate GABAA receptors in the absence of agonist. This has led to the hypothesis that general anesthetics produce anesthesia by enhancing GABAA receptor function (7).

Our results demonstrate that cyclopropane and butane significantly enhance agonist action only at concentrations that exceed those required to induce anesthesia and have little or no direct activating effect on {alpha}1ß2{gamma}2L GABAA receptors, even at aqueous saturating concentrations. The concentrations of anesthetic that double the current elicited by EC5 GABA are 6.4 ± 0.4 MAC for cyclopropane and 4.1 ± 0.2 MAC for butane. This is substantially larger than the 0.39 ± 0.03 MAC for isoflurane. When normalized to their hydrophobicities, cyclopropane and butane are 14- and 40-fold, respectively, less potent than isoflurane because the product of the concentration required to double the control current and the oil/aqueous partition coefficient is 250 for cyclopropane and 715 for butane as compared with just 18 for isoflurane (21,23).

In previous studies characterizing anesthetic action on {alpha}1ß2{gamma}2L GABAA receptors, anesthetic enhancement of agonist action has been shown to reflect a reduction in agonist EC50. For example, Scheller and Forman (15) observed that 2.7 MAC (0.75 mM) of isoflurane reduced the GABA EC50 of {alpha}1ß2{gamma}2L GABAA receptors by 71%. In the present study, we observed that at the near aqueous saturating concentrations that caused significant enhancement of agonist action, cyclopropane (12.2 MAC) and butane (6.3 MAC) also reduced the GABAA receptor’s agonist EC50. However, even at these very large MAC multiples, cyclopropane and butane induced a smaller reduction in the agonist EC50 (44% and 36%, respectively) than did 2.7 MAC of isoflurane.

Although our studies do not directly address the question of why nonhalogenated alkanes possess such small GABAA receptor potencies, we have previously noted that nonhalogenated alkanes cannot engage in electrostatic interactions (e.g., hydrogen bonding or dipolar interactions) with protein binding sites. Eckenhoff and Johansson (24) have suggested that hydrogen bonding interactions between an anesthetic and a protein binding site contributes ~1–1.5 kcal/mol of binding energy. This would increase anesthetic binding affinity by approximately an order of magnitude over that predicted by anesthetic hydrophobicity alone. This is consistent with our finding that when normalized to their oil/aqueous partition coefficients, isoflurane enhances agonist action on the GABAA receptor with a potency that is ~1–1.5 orders of magnitude larger than cyclopropane and butane.

Halogenated methylethyl ether and halogenated alkane anesthetics can inhibit currents mediated by GABAA receptors. Banks and Pearce (18) demonstrated that enflurane, isoflurane, and halothane reduce the amplitude of miniature inhibitory postsynaptic currents in a concentration-dependent manner. Although the physiological significance of this inhibitory action on GABAA receptors is not clear, they suggested that this action might contribute to the epileptogenic activities exhibited by some general anesthetics. This suggestion is based upon the observation that other GABAA receptor inhibitors such as picrotoxin and flurothyl cause seizures and is supported by their finding that enflurane, which is among the most epileptogenic of anesthetics, has a higher GABAA receptor inhibitory potency than either isoflurane or halothane (25–27). Fang et al. (28) have shown that nonhalogenated alkanes can also cause tremors or seizures. Our results demonstrating that two representative nonhalogenated alkanes fail to inhibit the most common GABAA receptor subtype in the brain even at aqueous saturating concentrations suggest that interactions with other targets account for the excitatory activities of nonhalogenated alkanes.

In summary, we have characterized the effects of cyclopropane and butane on heterologously expressed {alpha}1ß2{gamma}2L GABAA receptors. We found that at supraanesthetic concentrations, these anesthetics do enhance agonist action but have little or no direct activating or inhibiting activity, even at near aqueous saturating concentrations. These results suggest that nonhalogenated alkanes do not produce their neurobehavioral effects by either enhancing or inhibiting {alpha}1ß2{gamma}2L GABAA receptor function and are consistent with an important role for electrostatic interactions in defining GABAA receptor potency.


   Acknowledgments
 
Supported, in part, by the National Institutes of General Medical Sciences (RO1-GM61927).


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication September 10, 2002.




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R. J. N. Stevens, D. Rusch, P. A. Davies, and D. E. Raines
Molecular Properties Important for Inhaled Anesthetic Action on Human 5-HT3A Receptors
Anesth. Analg., June 1, 2005; 100(6): 1696 - 1703.
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D. E. Raines, F. Gioia, R. J. Claycomb, and R. J. Stevens
The N-Methyl-D-aspartate Receptor Inhibitory Potencies of Aromatic Inhaled Drugs of Abuse: Evidence for Modulation by Cation-{pi} Interactions
J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 14 - 21.
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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