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Edmond I. Eger - One of the best experts on this subject based on the ideXlab platform.
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Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled Anesthetics on conditioned
2016Co-Authors: James M Sonner, Mike Cascio, Yilei Xing, Michael S. Fanselow, Jason E. Kralic, Esa R. Korpi, Steven Hardy, Brian Sloat, Leslie A. Morrow, Edmond I. EgerAbstract:Inhaled Anesthetics are believed to produce anesthesia by their actions on ion channels. Because inhaled Anesthetics robustly enhance GABA A receptor (GABAA-R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABAA-Rs and individual GABAA-R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. We hypothesized that inhaled Anesthetics produce amnesia, as assessed by loss of fear conditioning, by acting on the forebrain GABAA-Rs that harbor the 1 subunit. To test this, we used global knockout mice that completely lack the 1 subunit and forebrain-specific, conditional knockout mice that lack the 1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145 % less sensitive to the amnestic effects of the inhale
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inhaled Anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats
Anesthesia & Analgesia, 2008Co-Authors: Edmond I. Eger, Douglas E Raines, Ken Solt, Jan F. A. Hendrickx, Andrew Jenkins, Michael J. Laster, Pamela Flood, Michael Tang, Mark Liao, Steven L. ShaferAbstract:BACKGROUND: We hypothesized that pairs of inhaled Anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that Anesthetics act on multiple sites to produce anesthesia. METHODS: Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By “divergently,” we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and -aminobutyric acid type A, glycine, N-methyl-d-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-d-aspartic acid blocker MK-801 had divergent effects on the MACs of these Anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane. RESULTS: All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found. CONCLUSIONS: Such results are consistent with the notion that inhaled Anesthetics act on a single site to produce immobility in the face of noxious stimulation. (Anesth Analg 2008;107:479‐85)
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do n methyl d aspartate receptors mediate the capacity of inhaled Anesthetics to suppress the temporal summation that contributes to minimum alveolar concentration
Anesthesia & Analgesia, 2006Co-Authors: Robert C. Dutton, Douglas E Raines, James M Sonner, Ken Solt, Michael J. Laster, Yilei Xing, Edmond I. EgerAbstract:Antagonism of N-methyl-d-aspartate (NMDA) receptors markedly decreases the minimum alveolar concentration (MAC) of inhaled Anesthetics. To assess the importance of suppression of the temporal summation NMDA receptor component of MAC, we stimulated the tail of rats with trains of electrical pulses of varying interstimulus intervals (ISIs) and determined the inhaled anesthetic concentrations (crossover concentrations) that suppressed movement at different ISIs. The slopes of crossover concentrations versus ISIs provided a measure of temporal summation for each anesthetic. We studied five Anesthetics that differ widely in their in vitro capacity to block NMDA receptors. To block NMDA receptor transmission and reveal the NMDA receptor component, the NMDA receptor antagonist, MK801, was separately added during each anesthetic. Halothane, isoflurane, and hexafluorobenzene did not appreciably suppress the NMDA receptor components of temporal summation, which contributed to 21% to 29% of MAC (P < 0.05 for each). Xenon and o-difluorobenzene suppressed these components to 8% to 0%, respectively, of MAC (neither significant), consistent with their greater NMDA receptor blocking action in vitro. NMDA receptor blockade may contribute to the MAC produced by inhaled Anesthetics that potently inhibit NMDA receptors in vitro but not those that have a limited in vitro effect.
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Characteristics of anesthetic agents used for induction and maintenance of general anesthesia
American Journal of Health-system Pharmacy, 2004Co-Authors: Edmond I. EgerAbstract:PURPOSE: The characteristics of ideal intravenous (i.v.) and inhaled anesthetic agents; the rationale for inducing anesthesia with i.v. Anesthetics (particularly propofol); the rationale for inducing and maintaining anesthesia with inhaled Anesthetics; and the advantages and disadvantages of specific inhaled Anesthetics, namely, nitrous oxide, desflurane, halothane, isoflurane, and sevoflurane, are discussed. SUMMARY: Propofol has many characteristics of the ideal i.v. anesthetic, including a rapid, smooth induction of anesthesia and rapid clearance from the body. The use of an i.v. anesthetic such as propofol avoids the claustrophobia associated with the inhaled route. Inhaled Anesthetics are preferred for maintenance of anesthesia because they allow a more precise control of the anesthetic state and do so at low cost. The ideal inhaled anesthetic agent has ample potency and a low solubility in blood and tissues (rapid recovery from anesthesia), resists physical and metabolic degradation, and protects and does not injure vital tissues. It also does not cause seizures, respiratory irritation, or circulatory stimulation or deplete the ozone layer. It has a low acquisition cost. Nitrous oxide potency is too small to produce anesthesia by itself. Halothane is too soluble and poses a risk of severe hepatotoxicity. Desflurane, isoflurane, and sevoflurane are preferred because they have an adequate potency, appropriate solubility, and minimal to no risk for hepatotoxicity. CONCLUSION: The utilization choice among desflurane, isoflurane, and sevoflurane is made by weighing specific advantages and disadvantages of each agent. The primary determining factors for use are anesthetic potency and control, rate of anesthesia induction, clearance from the body, and adverse effects.
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minimum alveolar anesthetic concentration of fluorinated alkanols in rats relevance to theories of narcosis
Anesthesia & Analgesia, 1999Co-Authors: Edmond I. Eger, Michael J. Laster, Adron R Harris, Pompiliu Ionescu, Diane Gong, Tomas Hudlicky, Joan J Kendig, James R Trudell, Andrew PohorilleAbstract:The Meyer-Overton hypothesis predicts that the potency of conventional inhaled Anesthetics correlates inversely with lipophilicity: minimum alveolar anesthetic concentration (MAC) 3 the olive oil/gas partition coefficient equals a constant of approximately 1.82 6 0.56 atm (mean 6 sd), whereas MAC 3 the octanol/gas partition coefficient equals a constant of approximately 2.55 6 0.65 atm. MAC is the minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus in 50% of subjects. Although MAC 3 the olive oil/gas partition coefficient also equals a constant for normal alkanols from methanol through octanol, the constant (0.156 6 0.072 atm) is one-tenth that found for conventional Anesthetics, whereas the product for MAC 3 the octanol/gas partition coefficient (1.72 6 1.19) is similar to that for conventional Anesthetics. These normal alkanols also have much greater affinities for water (saline/gas partition coefficients equaling 708 [octanol] to 3780 [methanol]) than do conventional Anesthetics. In the present study, we examined whether fluorination lowers alkanol saline/gas partition coefficients (i.e., decreases polarity) while sustaining or increasing lipid/gas partition coefficients, and whether alkanols with lower saline/gas partition coefficients had products of MAC 3 olive oil or octanol/gas partition coefficients that approached or exceeded those of conventional Anesthetics. Fluorination decreased saline/gas partition coefficients to as low as 0.60 6 0.08 (CF3[CF2]6CH2OH) and, as hypothesized, increased the product of MAC 3 the olive oil or octanol/gas partition coefficients to values equaling or exceeding those found for conventional Anesthetics. We conclude that the greater potency of many alkanols (greater than would be predicted from conventional inhaled Anesthetics and the Meyer-Overton hypothesis) is associated with their greater polarity. Implications: Inhaled anesthetic potency correlates with lipophilicity, but potency of common alkanols is greater than their lipophilicity indicates, in part because alkanols have a greater hydrophilicity— i.e., a greater polarity. (Anesth Analg 1999;88:867‐76)
Nicholas P Franks - One of the best experts on this subject based on the ideXlab platform.
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two pore domain k channels are a novel target for the anesthetic gases xenon nitrous oxide and cyclopropane
Molecular Pharmacology, 2004Co-Authors: Marco Gruss, Trevor J Bushell, Damian P Bright, W R Lieb, Alistair Mathie, Nicholas P FranksAbstract:Nitrous oxide, xenon, and cyclopropane are anesthetic gases that have a distinct pharmacological profile. Whereas the molecular basis for their anesthetic actions remains unclear, they behave very differently to most other general Anesthetics in that they have little or no effect on GABAA receptors, yet strongly inhibit the N-methyl-d-aspartate subtype of glutamate receptors. Here we show that certain members of the two-pore-domain K+ channel superfamily may represent an important new target for these gaseous Anesthetics. TREK-1 is markedly activated by clinically relevant concentrations of nitrous oxide, xenon, and cyclopropane. In contrast, TASK-3, a member of this family that is very sensitive to volatile Anesthetics, such as halothane, is insensitive to the anesthetic gases. We demonstrate that the C-terminal cytoplasmic domain is not an absolute requirement for the actions of the gases, although it clearly plays an important modulatory role. Finally, we show that Glu306, an amino acid that has previously been found to be important in the modulation of TREK-1 by arachidonic acid, membrane stretch and internal pH, is critical for the activating effects of the anesthetic gases.
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Structural basis for the inhibition of firefly luciferase by a general anesthetic.
Biophysical journal, 1998Co-Authors: Nicholas P Franks, Elena Conti, Andrew Jenkins, William R. Lieb, Peter BrickAbstract:The firefly luciferase enzyme from Photinus pyralis is probably the best-characterized model system for studying anesthetic-protein interactions. It binds a diverse range of general Anesthetics over a large potency range, displays a sensitivity to Anesthetics that is very similar to that found in animals, and has an anesthetic sensitivity that can be modulated by one of its substrates (ATP). In this paper we describe the properties of bromoform acting as a general anesthetic (in Rana temporaria tadpoles) and as an inhibitor of the firefly luciferase enzyme at high and low ATP concentrations. In addition, we describe the crystal structure of the low-ATP form of the luciferase enzyme in the presence of bromoform at 2.2-A resolution. These results provide a structural basis for understanding the anesthetic inhibition of the enzyme, as well as an explanation for the ATP modulation of its anesthetic sensitivity.
Adron R Harris - One of the best experts on this subject based on the ideXlab platform.
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effects of gaseous Anesthetics nitrous oxide and xenon on ligand gated ion channels comparison with isoflurane and ethanol
Anesthesiology, 2000Co-Authors: Tomohiro Yamakura, Adron R HarrisAbstract:BackgroundLigand-gated ion channels are considered to be potential general anesthetic targets. Although most general Anesthetics potentiate the function of γ-aminobutyric acid receptor type A (GABAA), the gaseous Anesthetics nitrous oxide and xenon are reported to have little effect on GABAA recepto
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amino acid volume and hydropathy of a transmembrane site determine glycine and anesthetic sensitivity of glycine receptors
Journal of Biological Chemistry, 1999Co-Authors: Tomohiro Yamakura, John S Mihic, Adron R HarrisAbstract:Abstract Two specific amino acid residues in transmembrane segments (TM) 2 and 3 are critical for the enhancement of glycine receptor (GlyR) function by volatile Anesthetics. To determine which physicochemical characteristics of these sites determine their roles in anesthetic actions, an extensive series of single amino acid mutations at amino acid residue 288 (Ala-288) in TM3 of the α1 GlyR subunit was tested for modulation by volatile Anesthetics. The mutations changed the apparent affinities of receptors for glycine; replacements with larger volumes and less hydropathy exhibited higher affinities for glycine. Potentiation by Anesthetics was reduced by specific mutations at Ala-288. The molecular volume of the substituents was negatively correlated with the extent of potentiation by isoflurane, enflurane, and 1-chloro-1,2,2-trifluorocyclobutane, whereas there was no correlation between anesthetic enhancement and polarity, hydropathy, or hydrophilicity of substituents. In contrast to Anesthetics, no correlation was found between the effects of the nonAnesthetics 1,2-dichlorohexafluorocyclobutane or 2,3-dichlorooctafluorobutane and any physicochemical property of the substituent. These results suggest that the molecular volume and hydropathy of the amino acid at position 288 in TM3 regulate glycine and anesthetic sensitivity of the GlyR and that this residue might represent one determinant of an anesthetic binding site.
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minimum alveolar anesthetic concentration of fluorinated alkanols in rats relevance to theories of narcosis
Anesthesia & Analgesia, 1999Co-Authors: Edmond I. Eger, Michael J. Laster, Adron R Harris, Pompiliu Ionescu, Diane Gong, Tomas Hudlicky, Joan J Kendig, James R Trudell, Andrew PohorilleAbstract:The Meyer-Overton hypothesis predicts that the potency of conventional inhaled Anesthetics correlates inversely with lipophilicity: minimum alveolar anesthetic concentration (MAC) 3 the olive oil/gas partition coefficient equals a constant of approximately 1.82 6 0.56 atm (mean 6 sd), whereas MAC 3 the octanol/gas partition coefficient equals a constant of approximately 2.55 6 0.65 atm. MAC is the minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus in 50% of subjects. Although MAC 3 the olive oil/gas partition coefficient also equals a constant for normal alkanols from methanol through octanol, the constant (0.156 6 0.072 atm) is one-tenth that found for conventional Anesthetics, whereas the product for MAC 3 the octanol/gas partition coefficient (1.72 6 1.19) is similar to that for conventional Anesthetics. These normal alkanols also have much greater affinities for water (saline/gas partition coefficients equaling 708 [octanol] to 3780 [methanol]) than do conventional Anesthetics. In the present study, we examined whether fluorination lowers alkanol saline/gas partition coefficients (i.e., decreases polarity) while sustaining or increasing lipid/gas partition coefficients, and whether alkanols with lower saline/gas partition coefficients had products of MAC 3 olive oil or octanol/gas partition coefficients that approached or exceeded those of conventional Anesthetics. Fluorination decreased saline/gas partition coefficients to as low as 0.60 6 0.08 (CF3[CF2]6CH2OH) and, as hypothesized, increased the product of MAC 3 the olive oil or octanol/gas partition coefficients to values equaling or exceeding those found for conventional Anesthetics. We conclude that the greater potency of many alkanols (greater than would be predicted from conventional inhaled Anesthetics and the Meyer-Overton hypothesis) is associated with their greater polarity. Implications: Inhaled anesthetic potency correlates with lipophilicity, but potency of common alkanols is greater than their lipophilicity indicates, in part because alkanols have a greater hydrophilicity— i.e., a greater polarity. (Anesth Analg 1999;88:867‐76)
Michael J. Laster - One of the best experts on this subject based on the ideXlab platform.
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inhaled Anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats
Anesthesia & Analgesia, 2008Co-Authors: Edmond I. Eger, Douglas E Raines, Ken Solt, Jan F. A. Hendrickx, Andrew Jenkins, Michael J. Laster, Pamela Flood, Michael Tang, Mark Liao, Steven L. ShaferAbstract:BACKGROUND: We hypothesized that pairs of inhaled Anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that Anesthetics act on multiple sites to produce anesthesia. METHODS: Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By “divergently,” we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and -aminobutyric acid type A, glycine, N-methyl-d-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-d-aspartic acid blocker MK-801 had divergent effects on the MACs of these Anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane. RESULTS: All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found. CONCLUSIONS: Such results are consistent with the notion that inhaled Anesthetics act on a single site to produce immobility in the face of noxious stimulation. (Anesth Analg 2008;107:479‐85)
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do n methyl d aspartate receptors mediate the capacity of inhaled Anesthetics to suppress the temporal summation that contributes to minimum alveolar concentration
Anesthesia & Analgesia, 2006Co-Authors: Robert C. Dutton, Douglas E Raines, James M Sonner, Ken Solt, Michael J. Laster, Yilei Xing, Edmond I. EgerAbstract:Antagonism of N-methyl-d-aspartate (NMDA) receptors markedly decreases the minimum alveolar concentration (MAC) of inhaled Anesthetics. To assess the importance of suppression of the temporal summation NMDA receptor component of MAC, we stimulated the tail of rats with trains of electrical pulses of varying interstimulus intervals (ISIs) and determined the inhaled anesthetic concentrations (crossover concentrations) that suppressed movement at different ISIs. The slopes of crossover concentrations versus ISIs provided a measure of temporal summation for each anesthetic. We studied five Anesthetics that differ widely in their in vitro capacity to block NMDA receptors. To block NMDA receptor transmission and reveal the NMDA receptor component, the NMDA receptor antagonist, MK801, was separately added during each anesthetic. Halothane, isoflurane, and hexafluorobenzene did not appreciably suppress the NMDA receptor components of temporal summation, which contributed to 21% to 29% of MAC (P < 0.05 for each). Xenon and o-difluorobenzene suppressed these components to 8% to 0%, respectively, of MAC (neither significant), consistent with their greater NMDA receptor blocking action in vitro. NMDA receptor blockade may contribute to the MAC produced by inhaled Anesthetics that potently inhibit NMDA receptors in vitro but not those that have a limited in vitro effect.
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minimum alveolar anesthetic concentration of fluorinated alkanols in rats relevance to theories of narcosis
Anesthesia & Analgesia, 1999Co-Authors: Edmond I. Eger, Michael J. Laster, Adron R Harris, Pompiliu Ionescu, Diane Gong, Tomas Hudlicky, Joan J Kendig, James R Trudell, Andrew PohorilleAbstract:The Meyer-Overton hypothesis predicts that the potency of conventional inhaled Anesthetics correlates inversely with lipophilicity: minimum alveolar anesthetic concentration (MAC) 3 the olive oil/gas partition coefficient equals a constant of approximately 1.82 6 0.56 atm (mean 6 sd), whereas MAC 3 the octanol/gas partition coefficient equals a constant of approximately 2.55 6 0.65 atm. MAC is the minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus in 50% of subjects. Although MAC 3 the olive oil/gas partition coefficient also equals a constant for normal alkanols from methanol through octanol, the constant (0.156 6 0.072 atm) is one-tenth that found for conventional Anesthetics, whereas the product for MAC 3 the octanol/gas partition coefficient (1.72 6 1.19) is similar to that for conventional Anesthetics. These normal alkanols also have much greater affinities for water (saline/gas partition coefficients equaling 708 [octanol] to 3780 [methanol]) than do conventional Anesthetics. In the present study, we examined whether fluorination lowers alkanol saline/gas partition coefficients (i.e., decreases polarity) while sustaining or increasing lipid/gas partition coefficients, and whether alkanols with lower saline/gas partition coefficients had products of MAC 3 olive oil or octanol/gas partition coefficients that approached or exceeded those of conventional Anesthetics. Fluorination decreased saline/gas partition coefficients to as low as 0.60 6 0.08 (CF3[CF2]6CH2OH) and, as hypothesized, increased the product of MAC 3 the olive oil or octanol/gas partition coefficients to values equaling or exceeding those found for conventional Anesthetics. We conclude that the greater potency of many alkanols (greater than would be predicted from conventional inhaled Anesthetics and the Meyer-Overton hypothesis) is associated with their greater polarity. Implications: Inhaled anesthetic potency correlates with lipophilicity, but potency of common alkanols is greater than their lipophilicity indicates, in part because alkanols have a greater hydrophilicity— i.e., a greater polarity. (Anesth Analg 1999;88:867‐76)
Andrew Jenkins - One of the best experts on this subject based on the ideXlab platform.
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inhaled Anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats
Anesthesia & Analgesia, 2008Co-Authors: Edmond I. Eger, Douglas E Raines, Ken Solt, Jan F. A. Hendrickx, Andrew Jenkins, Michael J. Laster, Pamela Flood, Michael Tang, Mark Liao, Steven L. ShaferAbstract:BACKGROUND: We hypothesized that pairs of inhaled Anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that Anesthetics act on multiple sites to produce anesthesia. METHODS: Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By “divergently,” we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and -aminobutyric acid type A, glycine, N-methyl-d-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-d-aspartic acid blocker MK-801 had divergent effects on the MACs of these Anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane. RESULTS: All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found. CONCLUSIONS: Such results are consistent with the notion that inhaled Anesthetics act on a single site to produce immobility in the face of noxious stimulation. (Anesth Analg 2008;107:479‐85)
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Structural basis for the inhibition of firefly luciferase by a general anesthetic.
Biophysical journal, 1998Co-Authors: Nicholas P Franks, Elena Conti, Andrew Jenkins, William R. Lieb, Peter BrickAbstract:The firefly luciferase enzyme from Photinus pyralis is probably the best-characterized model system for studying anesthetic-protein interactions. It binds a diverse range of general Anesthetics over a large potency range, displays a sensitivity to Anesthetics that is very similar to that found in animals, and has an anesthetic sensitivity that can be modulated by one of its substrates (ATP). In this paper we describe the properties of bromoform acting as a general anesthetic (in Rana temporaria tadpoles) and as an inhibitor of the firefly luciferase enzyme at high and low ATP concentrations. In addition, we describe the crystal structure of the low-ATP form of the luciferase enzyme in the presence of bromoform at 2.2-A resolution. These results provide a structural basis for understanding the anesthetic inhibition of the enzyme, as well as an explanation for the ATP modulation of its anesthetic sensitivity.