The Common Chemical Motifs Within Anesthetic Binding Sites

Bertaccini, Edward; Trudell, James R.; Franks, Nicholas P.

doi:10.1213/01.ane.0000253029.67331.8d

Cited by 46 publications

(68 citation statements)

References 31 publications

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“…Several protein structures that have been solved in the presence of anesthetics suggest that they may prefer amphipathic environments (61). Additionally, aromatic residues have been shown to interact with halothane in photo-labeling studies (13).…”

Section: Discussionmentioning

confidence: 99%

G Protein βγ Gating Confers Volatile Anesthetic Inhibition to Kir3 Channels

Styer

Mirshahi

Wang

et al. 2010

Journal of Biological Chemistry

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G protein-activated inwardly rectifying potassium (GIRK or Kir3) channels are directly gated by the ␤␥ subunits of G proteins and contribute to inhibitory neurotransmitter signaling pathways. Paradoxically, volatile anesthetics such as halothane inhibit these channels. We find that neuronal Kir3 currents are highly sensitive to inhibition by halothane. Given that Kir3 currents result from increased G␤␥ available to the channels, we asked whether reducing available G␤␥ to the channel would adversely affect halothane inhibition. Remarkably, scavenging G␤␥ using the C-terminal domain of ␤-adrenergic receptor kinase (c␤ARK) resulted in channel activation by halothane. Consistent with this effect, channel mutants that impair G␤␥ activation were also activated by halothane. A single residue, phenylalanine 192, occupies the putative G␤␥ gate of neuronal Kir3.2 channels. Mutation of Phe-192 at the gate to other residues rendered the channel non-responsive, either activated or inhibited by halothane. These data indicated that halothane predominantly interferes with G␤␥-mediated Kir3 currents, such as those functioning during inhibitory synaptic activity. Our report identifies the molecular correlate for anesthetic inhibition of Kir3 channels and highlights the significance of these effects in modulating neurotransmitter-mediated inhibitory signaling.Ion channels that control the excitability of neuronal conduction pathways are important targets for halogenated volatile anesthetics (HVAs) 4 (1, 2). HVAs such as halothane enhance the activity of inhibitory GABA A and glycine receptors and inhibit excitatory channels such as glutamate and nicotinic receptors (3). Several two-pore domain K (K 2 P) channels are activated by HVAs (4 -6). G protein-activated inwardly rectifying potassium (GIRK or Kir3) channels are also involved in inhibitory neurotransmission (7). Although ethanol and chloroform activate Kir3 channels (8, 9), paradoxically HVAs inhibit Kir3 channels (10, 11). Therefore, Kir3 channels present a rare case where an HVA such as halothane impairs inhibitory signaling by an ion channel.The exact mechanism for modulation of ion channels by volatile anesthetics is not fully clear (2). Two residues in the TM2 and TM3 of GABA A participate in regulating the effects of enflurane (12). In nicotinic receptors, sites of action for halothane on tyrosine residues near the channel pore were identified (13). The transmembrane domains in AMPA and NMDA receptors play critical roles in their anesthetics and ethanol sensitivity (14,15). Several sites on various K 2 P channels have been identified that are involved in anesthetic sensitivity (5, 16).Inhibitory neurotransmitters, exemplified by GABA, stimulate G␣ i/o -coupled receptors (17, 18) and liberate G␤␥ that directly activates Kir3 channels (19). Kir3 channels mediate slow inhibitory post-synaptic currents in central neurons, limiting neuronal excitability (7). Kir3-null mice show increased seizure susceptibility (20), hyperalgesia (21), and reduced neurotransmitter-, morphine...

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Section: Discussionmentioning

confidence: 99%

G Protein βγ Gating Confers Volatile Anesthetic Inhibition to Kir3 Channels

Styer

Mirshahi

Wang

et al. 2010

Journal of Biological Chemistry

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“…Receptor mutation studies suggest that high-affinity propofol binding of GABA A receptors occurs at sites that are distinctly different from those that bind low-affinity volatile anesthetics, such as isoflurane [2] . Low-affinity binding sites are postulated to be amphipathic and water filled pockets within the receptor [3,4] . At least in the case of N-methyl-D-aspartate (NMDA) receptors, this low-affinity protein binding is subject to a cut-off effect associated with molar water solubility, but not molecular structure or size [5] .…”

Section: Introductionmentioning

confidence: 99%

GABA<sub>A</sub> Receptor Modulation by Phenyl Ring Compounds Is Associated with a Water Solubility Cut-Off Value

Brosnan

Pham²

2016

Pharmacology

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Background: The modulation of N-methyl-D-aspartate receptors is associated with a molar water solubility cut-off effect of approximately 1.1 mmol/l and hence are unaffected by significantly less soluble compounds. However, compounds with this molar water solubility are still able to modulate γ-aminobutyric acid type A (GABA_A) receptors. We hypothesized that GABA_A receptor modulation by phenolic compounds would exhibit cut-off at a molar water solubility value less than 1.1 mmol/l. Methods: GABA_A receptors consisting of human α₁ and rat β₂ and γ_2s subunits were expressed in Xenopus laevis oocytes, and drug responses were measured using standard 2-electrode voltage clamp techniques. Twenty substituted phenols and benzenes of similar size and molecular volume were studied at saturated aqueous concentrations. Reversible and statistically significant change in GABA_A receptor current that was 10% or greater in magnitude from the baseline response defined a positive drug effect. Results: All phenyl ring compounds with a molar water solubility value equal to or greater than 0.46 mmol/l positively modulated GABA_A receptor currents. No compounds with a molar water solubility value equal to or less than 0.10 mmol/l had any effect on GABA_A receptor currents. Saturated solutions of phenols with 2,6-dimethyl and 2,6-diisopropyl substituents also caused channel opening in the absence of GABA. Conclusions: The molar water solubility cut-off for GABA_A receptor modulation by phenyl ring compounds lies between 0.10 and 0.46 mmol/l. Data suggest that hydrocarbons, perhaps including inhaled anesthetics, might modulate GABA_A receptors by displacing water from one or more low-affinity amphipathic binding sites to induce conformational changes that increase ion conductance.

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“…Detailed analysis has shown that IGAs modulate synaptic transmission in the central nervous system, rather than axonal conduction, and the effects of IGAs are remarkably synapse-specific and may vary among agents. IGA effects on the brain circuitry involved in sleep (hypothalamicbrain stem-thalamic loops) and memory (hippocampusamygdala-cortical loops) are currently the subject of intense study (Franks, 2008).We now know that IGAs are in fact relatively selective, that they act by binding to proteins, and that they do so by occupying small cavities (Bertaccini et al, 2007). In many cases, the relevant proteins are ion channels, and the effect of IGA binding to these allosteric sites is to alter the gating of these channels by physiological stimuli, presumably by altering the thermodynamic equilibrium between open and closed states of the channel.…”

mentioning

confidence: 99%

“…We now know that IGAs are in fact relatively selective, that they act by binding to proteins, and that they do so by occupying small cavities (Bertaccini et al, 2007). In many cases, the relevant proteins are ion channels, and the effect of IGA binding to these allosteric sites is to alter the gating of these channels by physiological stimuli, presumably by altering the thermodynamic equilibrium between open and closed states of the channel.…”

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confidence: 99%

“…IGA binding that is provided by the displacement of bound water molecules from within the cavity (Bertaccini et al, 2007). TRPV1 was first identified and has been most thoroughly studied in nociceptive neurons in the sensory system (Caterina et al, 1997), in which TRPV1 basically functions as a "molecular sensor" and as an integrator of a variety of physical and chemical stimuli including heat, capsaicin (the active ingredient of hot peppers) and low pH.…”

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confidence: 99%

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Sensitization of Nociceptive Ion Channels by Inhaled Anesthetics—A Pain in the Gas?

Harrison

Nau²

2008

Mol Pharmacol

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A remarkable new article in this issue of Molecular Pharmacology (p. 1261) shows that the capsaicin-sensitive ion channel TRPV1 is sensitized to activation by chemical and physical stimuli in the presence of inhaled general anesthetics. This finding provides another example of an ion channel in which the anesthetic acts to modify channel gating. This may have important clinical implications in view of the role of TRPV1 in nociception.The casual reader of a major medical textbook in the 1970s (Cohen, 1975) would have been informed that inhaled general anesthetics (IGAs) were "nonspecific agents" that acted "in the bulk lipid phase of the membrane" to "increase membrane fluidity" and thereby act as "membrane stabilizers" to produce unconsciousness. Of course, this was all hogwash. All of the preceding statements in this paragraph are scientifically incorrect, logically inconsistent, or linguistic nonsense. Nevertheless, the lipid theory of general anesthesia (Seeman, 1972) had a life of its own, and those early heretics who challenged this medieval orthodoxy were sentenced to hard time in the funding dungeons, before the modern era of molecular pharmacology dawned and brought with it a new enlightenment in this area. The textbooks have since been completely rewritten (Evers and Crowder, 2001).A recent review of the area (Franks, 2008) shows that our understanding of the molecular pharmacology and neurophysiology of IGAs has come along in leaps and bounds since the 1970s. Detailed analysis has shown that IGAs modulate synaptic transmission in the central nervous system, rather than axonal conduction, and the effects of IGAs are remarkably synapse-specific and may vary among agents. IGA effects on the brain circuitry involved in sleep (hypothalamicbrain stem-thalamic loops) and memory (hippocampusamygdala-cortical loops) are currently the subject of intense study (Franks, 2008).We now know that IGAs are in fact relatively selective, that they act by binding to proteins, and that they do so by occupying small cavities (Bertaccini et al., 2007). In many cases, the relevant proteins are ion channels, and the effect of IGA binding to these allosteric sites is to alter the gating of these channels by physiological stimuli, presumably by altering the thermodynamic equilibrium between open and closed states of the channel.There are numerous important examples of ion channels in which gating has been shown to be modified by IGAs at clinically relevant concentrations. These include the GABA-A receptors, the N-methyl-D-aspartate subtype of glutamate receptors, voltage-gated Na ϩ channels, the "twin-pore" K ϩ channels (for review, see Franks and Lieb, 1994;Franks, 2008), and now the TRPV1 channel. The existence of IGA binding sites as cavities within ion channels was first suggested by mutagenesis experiments (Mihic et al., 1997), but numerous IGA binding sites have now been studied in proteins of known structure using highresolution techniques (Bhattacharya et al., 2000). The binding of IGAs in these cavities is stab...

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The Common Chemical Motifs Within Anesthetic Binding Sites

Abstract: Anesthetic binding to proteins involves amphipathic interactions.

Cited by 46 publications

References 31 publications

G Protein βγ Gating Confers Volatile Anesthetic Inhibition to Kir3 Channels

G Protein βγ Gating Confers Volatile Anesthetic Inhibition to Kir3 Channels

GABA<sub>A</sub> Receptor Modulation by Phenyl Ring Compounds Is Associated with a Water Solubility Cut-Off Value

Sensitization of Nociceptive Ion Channels by Inhaled Anesthetics—A Pain in the Gas?

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