G Protein-Coupled Receptors as Direct Targets of Inhaled Anesthetics

Ishizawa, Yumiko; Pidikiti, Ravindernath; Liebman, Paul A.; Eckenhoff, Roderic G.

doi:10.1124/mol.61.5.945

Cited by 51 publications

(39 citation statements)

References 35 publications

(41 reference statements)

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“…A blood alcohol level of 0.1%, the legal limit for driving in many US states, corresponds to a concentration of ~22 mM. Structural and biophysical studies of anesthetics bound to model proteins have defined the importance of both non-polar and polar groups in the binding sites of these molecules [19][20][21][22][23] and binding sites for alcohols will also posses such an amphipathic nature 18 .…”

Section: Introductionmentioning

confidence: 99%

Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster

Kruse

Zhao

Smith

et al. 2003

Nat Struct Mol Biol

211

265

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SummaryWe have solved the high-resolution crystal structure of the Drosophila melanogaster alcoholbinding protein LUSH in the complexes it forms with a series of short chain n-alcohols. LUSH is the first known non-enzyme protein with a defined in vivo alcohol-binding function. The structure of LUSH reveals a set of molecular interactions that define a specific alcohol-binding site. A group of amino acids, Thr57, Ser52 and Thr48 form a network of concerted hydrogen bonds between the protein and the alcohol that provide a structural motif to increase alcohol binding affinity at this site. This motif appears to be conserved in a number of mammalian ligand-gated ion channels that are directly implicated in the pharmacological effects of alcohol. Further, these sequences are found in regions of ion-channels that are known to infer alcohol sensitivity. We suggest the alcohol-binding site in LUSH represents a general model for alcohol-binding sites in proteins.

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Section: Introductionmentioning

confidence: 99%

Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster

Kruse

Zhao

Smith

et al. 2003

Nat Struct Mol Biol

211

265

View full text Add to dashboard Cite

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“…G-protein coupled receptors represent strong candidates for the action of local anesthetics since anesthetics have been demonstrated to affect G-protein signal transduction pathways (Hollmann et al, 2001;Ishizawa et al, 2002). Interestingly, tertiary amine local anesthetics were shown to interact with the 5-HT 1A receptor by inhibiting specific agonist and antagonist binding when used at clinically relevant concentrations .…”

Section: Membrane Biology Of Serotonin 1a Receptors: Receptor-cholestmentioning

confidence: 98%

The Serotonin1A A Receptor: A Representative Member of the Serotonin Receptor Family

2005

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1. Serotonin is an intrinsically fluorescent biogenic amine that acts as a neurotransmitter and is found in a wide variety of sites in the central and peripheral nervous system. Serotonergic signaling appears to play a key role in the generation and modulation of various cognitive and behavioral functions. 2. Serotonin exerts its diverse actions by binding to distinct cell surface receptors which have been classified into many groups. The serotonin1A (5-HT1A) receptor is the most extensively studied of the serotonin receptors and belongs to the large family of seven transmembrane domain G-protein coupled receptors. 3. The tissue and sub-cellular distribution, structural characteristics, signaling of the serotonin1A receptor and its interaction with G-proteins are discussed. 4. The pharmacology of serotonin1A receptors is reviewed in terms of binding of agonists and antagonists and sensitivity of their binding to guanine nucleotides. 5. Membrane biology of 5-HT1A receptors is presented using the bovine hippocampal serotonin1A receptor as a model system. The ligand binding activity and G-protein coupling of the receptor is modulated by membrane cholesterol thereby indicating the requirement of cholesterol in maintaining the receptor organization and function. This, along with the reported detergent resistance characteristics of the receptor, raises important questions on the role of membrane lipids and domains in the function of this receptor.

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“…The list of proteins associated with lipid rafts includes ligand-gated channels, G protein-coupled receptors, and members of the SNARE complex (24,41,44). Each of these has been postulated to be a target of volatile anesthetics (16,18,45). Because rafts form a complex containing both lipids and proteins, it is possible that volatile anesthetics can perturb specific protein complexes embedded in this unique lipid milieu.…”

Section: Discussionmentioning

confidence: 99%

A stomatin and a degenerin interact in lipid rafts of the nervous system of Caenorhabditis elegans

Sedensky

Siefker

Koh³

et al. 2004

American Journal of Physiology-Cell Physiology

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In Caenorhabditis elegans, the gene unc-1 controls anesthetic sensitivity and normal locomotion. The protein UNC-1 is a close homolog of the mammalian protein stomatin and is expressed primarily in the nervous system. Genetic studies in C. elegans have shown that the UNC-1 protein interacts with a sodium channel subunit, UNC-8. In humans, absence of stomatin is associated with abnormal sodium and potassium levels in red blood cells. Stomatin also has been postulated to participate in the formation of lipid rafts, which are membrane microdomains associated with protein complexes, cholesterol, and sphingolipids. In this study, we isolated a low-density, detergent-resistant fraction from cell membranes of C. elegans. This fraction contains cholesterol, sphingolipids, and protein consistent with their identification as lipid rafts. We then probed Western blots of protein from the rafts and found that the UNC-1 protein is almost totally restricted to this fraction. The UNC-8 protein is also found in rafts and coimmunoprecipitates UNC-1. A second stomatin-like protein, UNC-24, also affects anesthetic sensitivity, is found in lipid rafts, and regulates UNC-1 distribution. Mutations in the unc-24 gene alter the distribution of UNC-1 in lipid rafts. Each of these mutations alters anesthetic sensitivity in C. elegans. Because lipid rafts contain many of the putative targets of volatile anesthetics, they may represent a novel class of targets for volatile anesthetics.

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G Protein-Coupled Receptors as Direct Targets of Inhaled Anesthetics

Cited by 51 publications

References 35 publications

Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster

Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster

The Serotonin1A A Receptor: A Representative Member of the Serotonin Receptor Family

A stomatin and a degenerin interact in lipid rafts of the nervous system of Caenorhabditis elegans

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