JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Walcourt, A.
Right arrow Articles by Nash, H. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Walcourt, A.
Right arrow Articles by Nash, H. A.
Related Collections
Right arrow Mechanisms
Anesth Analg 2001;92:535-541
© 2001 International Anesthesia Research Society

GENERAL ARTICLES

Blockage of One Class of Potassium Channel Alters the Effectiveness of Halothane in a Brain Circuit of Drosophila

Asikiya Walcourt, PhD, Robert L. Scott, BS, and Howard A. Nash, MD, PhD

Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, Maryland

Address correspondence and reprint requests to Howard A. Nash, MD, PhD, Bldg. 36, Rm. 1B08, LMB, NIMH, Bethesda MD 20892-4034.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
At concentrations comparable to those used in the clinic, halothane has profound effects on a neuronal pathway devoted to the escape reflex of the fruit fly, Drosophila melanogaster. We studied the influence of the potassium channel that is encoded by the Shaker gene on the halothane sensitivity of this circuit. Shaker channels were specifically inactivated either by genetic means, using strains with two different severe Shaker mutations, or by pharmacologic means, using ingestion of millimolar concentrations of 4-aminopyridine. In all cases, halothane potency decreased substantially. To ensure that the genetic alteration was specific, both mutations were studied as stocks that had been repeatedly backcrossed to a control strain. The specificity of the pharmacologic inhibition was demonstrated by the fact that 4-aminopyridine had no effect on halothane potency in a Shaker mutant. Quantitative differences in the effects of channel inhibition between males and females suggested a sexual dimorphism in the functional brain anatomy of the reflex circuit.

Implications: Shaker channels are important elements during halothane inhibition of a specific reflex in Drosophila. Neurons that express these channels, which are irregularly distributed in the brain of flies, provide promising leads to identifying anesthetic-sensitive components.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Potassium channels have long been regarded as highly relevant to general anesthesia [for recent reviews, see (1,2)]. This is because, under physiological conditions, efflux of potassium tends to hyperpolarize resting cells and to repolarize cells that are undergoing action potentials. Thus, the normal operation of potassium channels should modulate the effectiveness of anesthetics in altering excitability. Moreover, anesthetics can act directly on potassium channels. There are several kinds of potassium channels: anesthetics inhibit some and open others. Such perturbations of channel function could underlie some of the clinically relevant effects of these anesthetics. Although all of these possibilities are intriguing, there have been few studies that assess the impact of potassium channels on anesthesia in an intact organism.

The fruit fly, Drosophila melanogaster, provides one way to study the interplay between potassium channels and general anesthetics in a living whole animal. Previous work has shown that this tiny insect loses motor and postural control at concentrations of volatile anesthetics comparable to those used in the clinic (3,4). Of particular interest are the effects of anesthetics on the escape reflex, the insect equivalent of the startle response of vertebrates (5). The brain circuitry of this reflex can be monitored, as described in detail below, by a long-latency response to electrical stimulation. Previous work from our laboratory has shown that this circuit is as sensitive to general anesthetics as are gross postural and motor behaviors of the intact insect (6). Importantly, the anesthetic-sensitive locus of this reflex involves only a specific portion of the fly brain: mutants that disrupt much of the anatomy of the central brain do not alter the escape response or its sensitivity to anesthetics (7). In this work, we have used genetic and pharmacologic means to test the influence of a particular potassium channel on the potency of halothane in inhibiting this reflex. We thereby address the question of the relevance of this channel for anesthetic action in a circumscribed circuit of an intact animal.

The ion channel chosen for study is the one encoded by the Shaker (Sh) gene. In Drosophila, this channel is primarily responsible for IA, the rapidly inactivating outward current that follows depolarization (1,2). This current is physiologically significant. Elimination of it by genetic or pharmacologic means increases the excitability of Drosophila nerves, producing prolonged action potentials that result in enhanced release of neurotransmitter (8). Homologous channels are found in vertebrates, including humans, and have similar properties (9). A connection has long been known to exist between these channels and anesthesia: the Drosophila gene derives its name from the fact that, when exposed to diethyl ether, Sh mutants exhibit clonic leg twitching (8). However, this response appears to be a specific, local effect on excitability; it is seen in amputated legs (10) and is not seen when intact Sh flies are exposed to chloroform (10), halothane, isoflurane, or enflurane (DB Campbell and HAN, unpublished observations). Nevertheless, the strong contribution of these channels to neuromuscular physiology makes it of interest to examine the influence of Sh on halothane anesthesia.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All the fly stocks used in this work are congenic. That is, to eliminate adventitious mutations that might be present in the original mutant stock, each Sh allele was repeatedly backcrossed as described (11) to a Canton-S strain that had been marked with a mutation in forked (f), a nearby gene. After six rounds of backcrossing, individual f+ males were used to establish lines. These were screened for ether-induced leg-shaking to eliminate those lines in which the mutant allele had been lost by recombination in the interval between Sh and f. For each allele, a pool of six Sh lines was made; the resulting mutant stock was compared with the parental (f+) Canton-S stock.

The motor skills of wild-type and mutant stocks of flies in the absence and presence of anesthetic were measured with the distribution test, as described previously (11). Briefly, approximately 10 flies of a particular genotype were tapped to the bottom of a 50-mL conical centrifuge tube and the proportion that were able to climb out of the sloped base within 1 min was noted. In the absence of halothane, all flies of all of the stocks tested in this work passed the distribution test, i.e., none remained in the bottom of the vial. To determine anesthetic sensitivity, before performing the distribution test, the flies were exposed to a fixed concentration of halothane (Halocarbon Laboratories, River Edge, NJ) for 30–60 min. Note that, in contrast to the behavioral assay used in a previous study of Sh mutants and halothane (12), the preequilibration feature of the distribution test permits one to focus on changes in the effectiveness of anesthetics rather than changes in the speed with which they produce their effects. The concentration dependence of the proportion of flies at the bottom of the vial was used to determine a 50% effective concentration (EC50) and slope constant, as described below.

The escape response of the fruit fly can be elicited by application of a square wave across a pair of electrodes—one implanted in each eye—and monitored by electrophysiological recording from electrodes implanted in the jump and flight muscles (5). The motor output portion of the escape response circuit consists of a pair of giant neurons that conduct impulses from the brain to the thoracic ganglion, where they connect to interneurons and motoneurons that innervate the relevant muscles. The application of stimuli of modest intensity results in a characteristic latency, approximately 4 ms in duration, between the application of the square wave and the appearance of muscle potentials. This is the hallmark of a neuronal pathway that connects the visual system and the giant fiber circuit (6,13). In contrast to the response with a latency of approximately 1 ms that results from direct stimulation of the giant fiber by stronger stimuli, the 4-ms (long-latency) response is quite sensitive to halothane (6).

The apparatus used to deliver a flow of anesthetic-containing air while monitoring this response (14), and the standard testing protocol (7,14), have been described previously. This involved a preliminary test in the absence of anesthetic to ensure that the long-latency response was robust, followed by a 1-h exposure to a fixed concentration of halothane, and then a determination of the number of responses elicited by 10 stimuli. Typically, the fly was then subjected to one or two additional rounds of exposure to a larger concentration of halothane followed by testing with 10 stimuli. The concentration-response data resulting from 12–25 such observances were fit as described (7) to the standard logistic formula (15) to derive an EC50, the concentration at which half the stimuli fail to induce a response, and a slope constant, the measure of the steepness of the concentration-response curve. After the final test, the concentration of anesthetic was reduced to zero. In all cases, the long-latency response was restored, usually after 45–60 min of washout, although 75–90 min were required when the fly had been previously exposed to halothane concentrations much above 1% (v/v). The times for equilibration and washout are comparable with those required to achieve steady effects of anesthetics on behavior in flies at concentrations comparable with those used in the clinic (4,11). These times presumably reflect pharmacokinetic limitation of exchange of anesthetic gases between the exterior and interior of the fly, because larger concentrations of anesthetic produce similar responses in shorter times (4).

The procedure for administration of 4-aminopyridine (4-AP) followed a previously described protocol (16). Briefly, 3–6-day-old flies were transferred from food vials to empty vials and starved for 7 h. They were then transferred to a vial that contained at the bottom a piece of filter paper impregnated with a solution (adjusted to pH 7.1) containing 2% sucrose and various concentrations of 4-AP (Sigma Chemical, St. Louis, MO). The vial was plugged at the top with a rayon ball impregnated with the same solution, and the flies were allowed to feed for approximately 12 h. As reported previously (16), ingestion of millimolar concentrations of 4-AP caused Canton-S flies to shake when exposed to 1% diethyl ether. This was never seen in untreated Canton-S flies but was observed in approximately 60% of the flies fed 1.0 mM of 4-AP. It should also be noted that flies fed 0.5 mM or 1.0 mM of 4-AP tolerated the treatment well, but many flies fed with 2.5 mM of 4-AP became very infirm and did not survive the feeding period. To test the effect of 4-AP on the long-latency escape response and its inhibition by halothane, at the end of the feeding period, flies were removed from the vials (without any exposure to anesthetic), placed in the monitoring apparatus (14), and tested as described above.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Although Sh channels are widespread in adult flies, Sh mutants are not debilitated. Their general health is attested by their success in passing the distribution test (11), an assay of coordinated climbing. Moreover, Sh mutations had only modest effects on halothane inhibition of this complex behavior. As shown in Figure 1, sensitivity to halothane increased by 10% to 35% in the mutant lines. One should not conclude from the absence of a large effect on the distribution test that the Sh gene is inconsequential for anesthesia. As discussed below, complex behaviors integrate many consequences of anesthetic action and can thus mask important effects on individual systems. Thus, in this report, the influence of Sh was determined on the more circumscribed neural pathway of the escape response.



View larger version (61K):
[in this window]
[in a new window]
  		Figure 1. The influence of Shaker (Sh) mutations on the potency of halothane in disrupting climbing behavior. Male or female flies were assayed by the distribution test after exposure to a series of concentrations of halothane. Concentration-response data were analyzed separately for males and females, yielding slope constants of 3.4 ± 0.4 and 4.2 ± 0.3, respectively. The corresponding 50% effective concentration (EC50) values, together with 95% confidence limits were plotted. *Potency is significantly different (at the 95% confidence level) relative to the Canton-S (wt) control.

 
In contrast to the mildly increased sensitivity to halothane in the distribution test, homozygous females from two Sh mutant lines had a markedly decreased sensitivity to halothane in the electrophysiologically monitored escape response ( Fig. 2A for representative data). Specifically, halothane EC50 was increased in the ShE62 and ShKS133 stocks by 70% and 85%, respectively, over that of wild-type control females (Fig. 2B). Heterozygotes bearing one X chromosome from a Sh mutant and one X chromosome from the congenic wild-type control had halothane potencies that were intermediate between the mutant and wild-type values (Fig. 2A,B). Thus, as with other Sh phenotypes (8), the anesthetic phenotype of both mutations tested was semidominant.



View larger version (22K):
[in this window]
[in a new window]
  		Figure 2. The influence of Shaker (Sh) mutations on the potency of halothane in inhibiting the long-latency escape response of female flies. A, Representative data for Canton-S wild-type (•), ShE62 homozygotes ({blacklozenge}), and Canton-S/ShE62 heterozygotes ({circ}). The number of failures from ten trials of the long-latency response values was plotted as a function of the concentration of halothane. B, 50% effective concentration (EC50) values, together with 95% confidence limits, for the strains shown in (A) plus ShKS133 homozygotes and heterozygotes. The concentration-response data for all of these strains were analyzed jointly; the resulting slope constant was 7.6 ± 0.6. *Potency is significantly different (at the 95% confidence level) relative to the Canton-S (wt) control.

 
Pharmacologic inhibition of Sh channels was achieved by feeding flies a specific inhibitor, 4-AP. When wild-type female flies were fed 0.5 or 1.0 mM of 4-AP, the potency of halothane was diminished, respectively, by 33% and 40% with respect to control flies ( Fig. 3). These controls, which were starved and refed sucrose without 4-AP, had an EC50 for halothane that was indistinguishable from that of untreated flies (Fig. 2 versus Fig. 3). The specificity of the drug effect was tested by feeding 4-AP to females of a Sh mutant line; EC50 was unaltered (Fig. 3).



View larger version (54K):
[in this window]
[in a new window]
  		Figure 3. The influence of 4-aminopyridine (4-AP) on the potency of halothane in inhibiting the long-latency escape response of female flies. After starvation, flies ingested food doped with the indicated concentration of 4-AP and the potency of halothane was then determined as in Figure 2. For the Canton-S (wt) strain, the slope constant for the three experiments shown was 9.2 ± 0.9. *Potency is significantly different (at the 95% confidence level) relative to the control refed with sucrose containing 0.0 mM of 4-AP. For the Shaker (Sh)KS133 strain, the slope constant for the two experiments shown was 7.2 ± 0.9. {dagger}Potency is not significantly different (at the 95% confidence level) relative to ShKS133 refed with sucrose containing 0.0 mM of 4-AP.

 
Compared with females, male flies have lower EC50 values for the effects of halothane on the long-latency escape response (Fig. 2 versus Fig. 4). From this lower baseline, EC50 undergoes an even larger change in males than in females (75% vs 33%) after ingestion of 0.5 mM of 4-AP (Fig. 4). Similarly, in male flies (Fig. 4), the ShE62 mutation produced a very large increase in EC50 (128% relative to Canton-S males) but the ShKS133 mutation had a more modest effect on EC50 (a 35% increase) than in females.



View larger version (46K):
[in this window]
[in a new window]
  		Figure 4. The influence of Shaker (Sh) mutations and 4-aminopyridine (4-AP) on the potency of halothane in inhibiting the long-latency escape response of male flies. All the concentration-response curves were analyzed jointly, yielding a slope constant of 5.4 ± 0.4 and the plotted 50% effective concentration (EC50) values. *Potency is significantly different (at the 95% confidence level) relative to the Canton-S (wt) control.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The data in this report lead us to conclude that, as judged by the operation of a particular neuronal pathway in the brain of the fruit fly, Sh channels are important determinants of halothane anesthesia. In arriving at this conclusion, the combination of genetics and pharmacology was particularly powerful. Performed in isolation, genetic studies are often unable to distinguish between effects of a mutation on a physiological process and effects of the mutation on development of the system devoted to the process. Thus, finding that Sh mutations alter anesthetic potency does not, by itself, show that channel function is important during anesthesia. For example, neural development is altered by hyperexcitability (17); halothane potency of the mutants could reflect altered development and have nothing to do with Sh currents during anesthesia. In a previous study of the influence of Sh on anesthesia in Drosophila (18), the authors attempted to address this question by expressing the wild-type protein during the adult life of a mutant. The decreased potency of isoflurane, as assayed by inhibition of movement in response to a noxious stimulus, which they had observed in Sh mutants, was not reversed by this stratagem. Although this suggests a developmental role for the Sh gene, the level of expression of the transgene was not determined, leaving the question open.

In the present case, the fact that feeding adult flies 4-AP, a blocker of Sh channels, produced a similar shift in halothane potency as that produced by Sh mutations, is strong evidence that a major portion of the mutant effect is on physiology rather than development. Because 4-AP can influence channels other than Sh (19), we considered whether such inhibition, rather than inhibition of Sh channels, is largely responsible for the 4-AP effect on halothane potency. If so, the drug should alter anesthetic potency in a Sh mutant, which is specifically defective in IA but not several other ion currents (8). The fact that there was no effect of 4-AP on halothane potency of a Sh mutant (Fig. 3) argues that the 4-AP effect on wild-type flies indeed reflects inhibition of Sh channels. It must be pointed out that inactivation of Sh channels by feeding 4-AP to adults generally had a smaller effect on halothane potency than did inactivation of these channels by mutation. This suggests that the mutants have additional, presumably developmental, effects. However, it is also possible that the smaller effect of 4-AP is because ingestion is self-limiting, and thereby fails to achieve concentrations of the drug necessary for complete inhibition of channel function. Nevertheless, taken together, the data in this report establish that halothane potency for inhibiting a brain circuit in adult flies reflects, at least in part, the functional status of Sh-encoded potassium channels.

In contrast to a robustly decreased halothane potency for the escape response circuit, Sh mutants were associated with a mildly increased potency of halothane in inhibiting a climbing behavior. Why is this so? Previously, we have discussed this paradox in detail (11). To recapitulate briefly, complex behaviors, such as climbing, combine many neural circuits. At a particular concentration, anesthetics may excite some of these circuits and depress others. Moreover, because anesthetics affect more than one neural component, a single mutation may influence anesthetic potency on some of these circuits more than others. The net result of these multiple influences can be that mutant effects on anesthetic potency of a complex behavior are very different from the mutant effect on a single circuit. In the present case, it may be that increased excitability of Sh flies makes them unsteady and thereby sensitizes them to effects of halothane on coordination. It is only by studying a simpler circuit that one has a hope of determining the interplay between anesthetics and a single neural component affected by a mutation.

There are two ways in which the contribution of Sh channels to adult physiology might influence the potency of halothane in inhibiting the escape response. These channels might be direct targets of volatile anesthetics, or their normal operation might influence safety factors of cells that contain anesthetic targets. Distinguishing between these possibilities (or if they are both operative, determining their relative contribution) would require examination of the individual neurons that make up the anesthetic-sensitive brain circuit. Although this cannot be done at present, our data set certain limits on each possibility. First, consider the possibility that Sh channels are direct targets for halothane. Indeed, several studies have shown that isolated Sh channels are inhibited by halothane, albeit with low potency (1,20). If this were responsible for halothane action in the pathway for the escape response, one would expect that Sh mutations and 4-AP would mimic halothane, and thus increase its potency. The fact that the opposite result is obtained is thus inconsistent with the model of halothane inhibition of Sh function. The decreased potency of halothane that is observed when Sh function is removed genetically or pharmacologically is consistent with the possibility that halothane enhances current through Sh channels. But, although halothane opens some kinds of potassium channels (21,22), this has not been observed with isoforms of Sh. It should be noted, however, that the Sh gene is subject to an unusually diverse pattern of splicing (23,24), and only a few of the isoforms have been examined for anesthetic effects. Also, the possible contribution of Sh channels to the safety factor for neural transmission through a cell containing an anesthetic target should be considered. Because reduction of IA increases excitability, in order to account for the decreased halothane potency after inactivation of Sh, the principal influence of these channels on the safety factor would have to be in cells that provide excitatory input to anesthetic-target neurons. In the Drosphila brain, these would be expected to be cholinergic (25,26). For either of the possibilities considered above, identifying the critical neurons should be facilitated by the restricted distribution of Sh channels within the fly brain. This is particularly the case for optic lobe, inferred in previous work as a principal component of the pathway for the escape reflex (7). For example, only one of nine layers of the optic medulla shows intense staining with an antibody to Sh protein, as does only one of three optic chiasmata (24). Manipulating expression and/or activity of Sh channels in these areas should be informative.

In this study, genetic and pharmacologic alteration of Sh function had qualitatively similar effects on halothane potency in male and female flies. But in virtually every case there was a significant quantitative difference between sexes. The issue is confounded by the fact that the halothane potency for inhibition of the long-latency response is different in wild-type males and females. Nevertheless, the observations suggest that, in a part of the brain used for the escape reflex, Sh channels are differentially used in males and females. Also of interest is the distinction between the sexes in the effect of the two Sh mutations. Based on previous data, one would expect that both mutations reduce Sh function drastically. The ShE62 mutation damages a splice site for the isoform that is commonly used in brain (23); in the absence of splicing, Sh encodes a channel with a truncated (and presumably nonfunctional) carboxy-terminus (8). The ShKS133 mutation replaces a highly conserved nonpolar residue in the presumptive pore region with a charged residue. This is expected to inactivate the channel and, where examined, has done so (8). Although these mutations have comparable and strong effects in females, in males the ShKS133 mutation has a smaller effect on halothane potency than that associated with ShE62 or that achieved by feeding 4-AP. Unless the ShKS133 mutation does not render the channel as inert as expected, the difference suggests that males are subject to compensatory changes in development that are particularly provoked by the ShKS133 mutation.

In summary, we have presented evidence that implicates Sh channels as important determinants of anesthesia in a specific brain circuit of Drosophila. Mechanistic possibilities for the relationship between halothane and Sh are limited by the known effect of these channels on excitability, and the observation that damage to them decreases halothane potency. The well established conservation of Sh channels (9) and the presumptive conservation of halothane targets (4) implies that a comparable interplay occurs in higher organisms.


   Acknowledgments
 
Meiqui Lin is acknowledged for the initial observations that prompted the construction of the strains used in this work. We thank George Kracke and David Sandstrom for their comments on this report.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Bosnjak ZJ, Kwok W-M, Pancrazio JJ. Potassium channels. In: Yaksh TL, Lynch C, Zapol WM, eds. Anesthesia: biologic foundations. Philadelphia: Lippincott-Raven, 1997: 197–219.
  2. Yost CS. Potassium channels: basic aspects, functional roles, and medical significance. Anesthesiology 1999; 90: 1186–203.[ISI][Medline]
  3. Gamo S, Ogaki M, Nakashima-Tanaka E. Strain differences in minimum anesthetic concentrations in Drosophila melanogaster. Anesthesiology 1981; 54: 289–93.[ISI][Medline]
  4. Allada R, Nash HA. Drosophila melanogaster as a model for study of general anesthesia: the quantitative response to clinical anesthetics and alkanes. Anesth Analg 1993; 77: 19–26.[Abstract/Free Full Text]
  5. Wyman RJ, Thomas JB, Salkoff L, King D. The Drosophila giant fiber system. In: Eaton R, ed. Neural mechanisms of startle behavior. New York: Plenum Publishing, 1984: 133–61.
  6. Lin M, Nash HA. Influence of general anesthetics on a specific neural pathway in Drosophila melanogaster. Proc Natl Acad Sci USA 1996; 93: 10446–51.[Abstract/Free Full Text]
  7. Walcourt A, Nash HA. Genetic effects on an anesthetic-sensitive pathway in the brain of Drosphila. J Neuobiol 2000; 42: 69–78.
  8. Wu C-F, Ganetzky B. Neurogenetic studies of ion channels in Drosophila. In: Narahashi T, ed. Ion channels. New York: Plenum Press, 1992: 261–314.
  9. Salkoff L, Baker K, Butler A, et al. An essential ‘set’ of K+ channels conserved in flies, mice and humans. Trends Neurosci 1992; 15: 161–6.[ISI][Medline]
  10. Ganetzky B, Wu C-F. Indirect suppression involving behavioral mutants with altered nerve excitability in Drosophila melanogaster. Genetics 1982; 100: 597–614.[Abstract/Free Full Text]
  11. Guan Z, Scott RL, Nash HA. A new assay for the genetic study of general anesthesia in Drosophila melanogaster: use in analysis of mutations in the 12E region. J Neurogenet 2000; 14: 25–42.[ISI][Medline]
  12. Leibovitch BA, Campbell DB, Krishnan KS, Nash HA. Mutations that affect ion channels change the sensitivity of Drosophila melanogaster to volatile anesthetics. J Neurogenet 1995; 10: 1–13.[ISI][Medline]
  13. Engel JE, Wu C-F. Altered habituation of an identified escape circuit in Drosophila memory mutants. J Neurosci 1996; 16: 3486–99.[Abstract/Free Full Text]
  14. Walcourt A, Ide D. A system for the delivery of general anesthetics and other volatile agents to the fruit fly Drosophila melanogaster. J Neurosci Methods 1998; 84: 115–9.[ISI][Medline]
  15. Waud DR. On biological assays involving quantal responses. J Pharmacol Exper Ther 1972; 183: 577–607.[Abstract/Free Full Text]
  16. Jan YN, Jan LY, Dennis MJ. Two mutations of synaptic transmission in Drosophila. Proc R Soc Lond B Biol Sci 1977; 198: 87–108.[Medline]
  17. Budnik V, Zhong Y, Wu CF. Morphological plasticity of motor axons in Drosophila mutants with altered excitability. J Neurosci 1990; 10: 3754–68.[Abstract]
  18. Tinklenberg JA, Segal IS, Guo TZ, Maze M. Analysis of anesthetic action on the potassium channels of the Shaker mutant of Drosophila. Ann NY Acad Sci 1991; 625: 532–9.[Abstract]
  19. Singh A, Singh S. Unmasking of a novel potassium current in Drosophilia by a mutation and drugs. J Neurosci 1999; 19: 6338–43.[Abstract/Free Full Text]
  20. Correa AM. Gating kinetics of Shaker K+ channels are differentially modified by general anesthetics. Am J Physiol 1998; 275: C1009–21.[Abstract/Free Full Text]
  21. Franks NP, Lieb WR. Background K+ channels: an important target for volatile anesthetics? Nat Neurosci 1999; 2: 395–6.[ISI][Medline]
  22. Sirois JE, Lei Q, Talley EM, et al. The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics. J Neurosci 2000; 20: 6347–54.[Abstract/Free Full Text]
  23. Hardie RC, Voss D, Pongs O, Laughlin SB. Novel potassium channels encoded by the Shaker locus in Drosophila photoreceptors. Neuron 1991; 6: 477–86.[ISI][Medline]
  24. Rogero O, Hammerle B, Tejedor FJ. Diverse expression and distribution of Shaker potassium channels during the development of the Drosophila nervous system. J Neurosci 1997; 17: 5108–18.[Abstract/Free Full Text]
  25. Gundelfinger ED. How complex is the nicotinic receptor system of insects? Trends Neurosci 1992; 15: 206–11.[ISI][Medline]
  26. Lee D, O’Dowd DK. Fast excitatory synaptic transmission mediated by nicotinic acetylcholine receptors in Drosophila neurons. J Neurosci 1999; 19: 5311–21.[Abstract/Free Full Text]
Accepted for publication October 11, 2000.




This article has been cited by other articles:


Home page
 Anesth. Analg.Home page
M. M. Sedensky and P. G. Morgan
Genetics and the Evolution of the Anesthetic Response
Anesth. Analg., September 1, 2008; 107(3): 855 - 858.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. Allada
An emerging link between general anesthesia and sleep
PNAS, February 19, 2008; 105(7): 2257 - 2258.
[Full Text] [PDF]

Home page
 Anesth. Analg.Home page
S. Rajaram and H. A. Nash
A Specific Alteration in the Electroretinogram of Drosophila melanogaster Is Induced by Halothane and Other Volatile General Anesthetics
Anesth. Analg., June 1, 2004; 98(6): 1705 - 1711.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. A. Humphrey, M. M. Sedensky, and P. G. Morgan
Understanding anesthesia: making genetic sense of the absence of senses
Hum. Mol. Genet., May 15, 2002; 11(10): 1241 - 1249.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Walcourt, A.
Right arrow Articles by Nash, H. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Walcourt, A.
Right arrow Articles by Nash, H. A.
Related Collections
Right arrow Mechanisms

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