The Role of Electrostatic Interactions in Governing Anesthetic Action on the Torpedo Nicotinic Acetylcholine Receptor

Raines, Douglas E.; Claycomb, Robert

doi:10.1213/00000539-200208000-00021

Cited by 5 publications

(6 citation statements)

References 22 publications

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“…Such traces were indistinguishable from those obtained using the lowest concentrations of halothane or sevoflurane studied, suggesting that cyclopropane acts on (Aα 2 -L1M/L38M) 2 , with low potency. Such anomalously low potency for cyclopropane in this model system would parallel that observed in functional studies using native and heterologously expressed Cys-loopLGICs (16,(39)(40)(41). For example, when normalized to their anesthetizing potencies, cyclopropane is an order of magnitude less potent than isoflurane at stabilizing the GABA A receptor in a conformational state that has increased sensitivity to agonist (16).…”

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confidence: 70%

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Kinetics of Anesthetic-Induced Conformational Transitions in a Four-α-Helix Bundle Protein

2006

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Inhaled anesthetics are thought to alter the conformational states of Cys-loop ligand-gated ion channels (LGICs) by binding within discrete cavities that are lined by portions of four α-helical transmembrane domains. Because Cys-loop LGICs are complex molecules that are notoriously difficult to express and purify, scaled-down models have been used to better understand the basic molecular mechanisms of anesthetic action. In this study, stopped-flow fluorescence spectroscopy was used to define the kinetics with which inhaled anesthetics interact with (Aα 2 -L1M/L38M) 2 , a four-α-helix bundle protein that was designed to model anesthetic binding sites on Cys-loop LGICs. Stopped-flow fluorescence traces obtained upon mixing (Aα 2 -L1M/L38M) 2 with halothane revealed immediate, fast, and slow components of quenching. The immediate component, which occurred within the mixing time of the spectrofluorimeter, was attributed to direct quenching of tryptophan fluorescence upon halothane binding to (Aα 2 -L1M/L38M) 2 . This was followed by a bi-exponential fluorescence decay containing fast and slow components, reflecting anesthetic-induced conformational transitions. Fluorescence traces obtained in studies using sevoflurane, isoflurane, and desflurane, which poorly quench tryptophan fluorescence, did not contain the immediate component. However, these anesthetics did produce the fast and slow components, indicating that they also alter the conformation of (Aα 2 -L1M/L38M) 2 . Cyclopropane, an anesthetic which acts with unusually low potency on Cys-loop LGICs, acted with low apparent potency on (Aα 2 -L1M/L38M) 2 . These results suggest that four-α-helix bundle proteins may be useful models of in-vivo sites of action that allow use of a wide range of techniques to better understand how anesthetic binding leads to changes in protein structure and function. KeywordsAnesthesia; Cyclopropane; Desflurane; Fluorescence; Halothane; Isoflurane; Kinetics; Sevoflurane; Spectroscopy; Stopped-flow Inhaled general anesthetics alter the function of numerous proteins (1-5). Although the receptor site(s) responsible for producing anesthesia are not known with certainty, members of an anesthetic-sensitive superfamily of homologous Cys-loop ligand-gated ion channels (LGICs) are believed to be among the most important targets (6-8). Members of this superfamily include the nicotinic acetylcholine, serotonin type 3, γ-aminobutyric acid type A (GABA A ), and † This work was supported by grants from the National Institutes of Health GM61927 and GM58448 for DER and GM55876 and GM65218 for JSJ LGICs are complex molecules that cannot be expressed in significant quantities and at high purity, there remain considerable obstacles to applying powerful biophysical and biochemical approaches to gain insight into how inhaled anesthetics act on these targets.To overcome these obstacles, small, water-soluble four-α-helix bundle proteins have been designed, produced, and used as well-defined model systems to explore how inhaled anesthetics bind to p...

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confidence: 70%

“…LGICs (16,(39)(40)(41). For example, when normalized to their anesthetizing potencies, cyclopropane is an order of magnitude less potent than isoflurane at stabilizing the GABA A receptor in a conformational state that has increased sensitivity to agonist (16).…”

Section: Resultsmentioning

confidence: 99%

Kinetics of Anesthetic-Induced Conformational Transitions in a Four-α-Helix Bundle Protein

2006

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“…For example, general anesthetics enhance agonist action on Torpedo nicotinic acetylcholine receptors with potencies that correlate with their abilities to form hydrogen-bonds and nonhalogenated alkanes, which are distinguished from most other anesthetics by their inability to engage in electrostatic interactions, enhance agonist action on GABA A receptors with potencies that are an order of magnitude lower than would be predicted by their hydrophobicities [2,9]. In conclusion, our results provide strong evidence that electrostatic cation-k interactions modulate the NMDA receptor inhibitory potencies of volatile anesthetics possessing k electron clouds.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is growing evidence that attractive electrostatic interactions between inhaled anesthetics and their receptor targets enhance anesthetic potency beyond that predicted by hydrophobicity alone [2]. Hydrogen-bonding is among the most recognized electrostatic interactions.…”

Section: Introductionmentioning

confidence: 99%

“…Hydrogen-bonding is among the most recognized electrostatic interactions. Previous studies using the firefly luciferase enzyme (an experimental model for studying anesthetic action on proteins) and the nicotinic acetylcholine receptor have shown that an anesthetic's potency is dependent upon its hydrogen-bonding capacity [2,3]. Cation-k interactions are similarly strong electrostatic interactions that occur between a k electron cloud and an atom that carries a full or partial positive charge.…”

Section: Introductionmentioning

confidence: 99%

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Cation–π interactions modulate the NMDA receptor inhibitory potencies of inhaled aromatic anesthetics

Raines

2005

International Congress Series

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Water in the human body: An anesthesiologist's perspective on the connection between physicochemical properties of water and physiologic relevance

Riveros-Pérez

Riveros

2018

Annals of Medicine and Surgery

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The unique structure and multifaceted physicochemical properties of the water molecule, in addition to its universal presence in body compartments, make water a key player in multiple biological processes in human physiology. Since anesthesiologists deal with physiologic processes where water molecules are critical at different levels, and administer medications whose pharmacokinetics and pharmacodynamics depend on interaction with water molecules, we consider that exploration of basic science aspects related to water and its role in physiology and pharmacology is relevant to the practice of anesthesiology. The purpose of this paper is to delineate the physicochemical basis of water that are critical in enabling it to support various homeostatic processes. The role of water in the formation of solutions, modulation of surface tension and in homeostasis of body temperature, acid-base status and osmolarity, is analyzed. Relevance of molecular water interactions to the anesthesiologist is not limited to the realm of physiology and pathophysiology. Deep knowledge of the importance of water in volatile anesthetic effects on neurons opens a window to a new comprehensive understanding of complex cellular mechanisms underlying the practice of anesthesiology.

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The Role of Electrostatic Interactions in Governing Anesthetic Action on the Torpedo Nicotinic Acetylcholine Receptor

Cited by 5 publications

References 22 publications

Kinetics of Anesthetic-Induced Conformational Transitions in a Four-α-Helix Bundle Protein

Kinetics of Anesthetic-Induced Conformational Transitions in a Four-α-Helix Bundle Protein

Cation–π interactions modulate the NMDA receptor inhibitory potencies of inhaled aromatic anesthetics

Water in the human body: An anesthesiologist's perspective on the connection between physicochemical properties of water and physiologic relevance

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