Insights into Distinct Modulation of α7 and α7β2 Nicotinic Acetylcholine Receptors by the Volatile Anesthetic Isoflurane

Mowrey, David D.; Liu, Qiang; Bondarenko, Vasyl; Chen, Qiang; Seyoum, Edom; Xu, Yan; Wu, Jie; Tang, Pei

doi:10.1074/jbc.m113.508333

Cited by 36 publications

(34 citation statements)

References 54 publications

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“…One difference that has been reported in the allosteric modulation of these two nAChR subtypes is that α7β2 receptors, but not α7 receptors, are inhibited by the volatile anaesthetic isoflurane [153]. On the basis of mutagenesis and computer docking studies, it has been proposed that isoflurane binds to the β2 transmembrane domain [153]. This is consistent with evidence for a transmembrane binding site for anaesthetics on other LGICs [154].…”

Section: Various Sites and Amino Acids Have Been Shown To Be Importanmentioning

confidence: 77%

“…Although the focus of this review has been the family of nAChRs, the evidence for the existence of multiple modulatory sites, both in transmembrane and extra-transmembrane locations is a feature that appears to be common amongst neurotransmitter-gated ion channels. X-ray crystallography and NMR [143,153,156,176] …”

Section: Discussionmentioning

confidence: 99%

“…However, in addition, it can co-assemble with β2 to form a heteromeric α7β2 complex [152]. One difference that has been reported in the allosteric modulation of these two nAChR subtypes is that α7β2 receptors, but not α7 receptors, are inhibited by the volatile anaesthetic isoflurane [153]. On the basis of mutagenesis and computer docking studies, it has been proposed that isoflurane binds to the β2 transmembrane domain [153].…”

Section: Various Sites and Amino Acids Have Been Shown To Be Importanmentioning

confidence: 98%

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Allosteric modulation of nicotinic acetylcholine receptors

Chatzidaki

Millar

2015

Biochemical Pharmacology

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Section: Various Sites and Amino Acids Have Been Shown To Be Importanmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Various Sites and Amino Acids Have Been Shown To Be Importanmentioning

confidence: 98%

See 1 more Smart Citation

Allosteric modulation of nicotinic acetylcholine receptors

Chatzidaki

Millar

2015

Biochemical Pharmacology

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“…Interestingly, a7b2 are highly sensitive to blockade by Ab1-42, suggesting that they may play a unique role in the neuropathology of Alzheimer disease (Liu et al, 2009). Additionally, these heteromeric receptors exhibit high sensitivity to volatile anesthetics, and therefore could be targets for anesthetic action (Mowrey et al, 2013). Thus, a7b2 nAChR may represent a novel molecular target requiring selective a7b2 ligands.…”

Section: Introductionmentioning

confidence: 99%

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

2016

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The nicotinic acetylcholine receptor (nAChR) belongs to a superfamily of pentameric ligand-gated ion channels involved in many physiologic and pathologic processes. Among nAChRs, receptors comprising the a7 subunit are unique because of their high Ca 21 permeability and fast desensitization. nAChR agonists elicit a transient ion flux response that is further sustained by the release of calcium from intracellular sources. Owing to the dual ionotropic/metabotropic nature of a7 receptors, signaling pathways are activated. The a7 subunit is highly expressed in the nervous system, mostly in regions implicated in cognition and memory and has therefore attracted attention as a novel drug target. Additionally, its dysfunction is associated with several neuropsychiatric and neurologic disorders, such as schizophrenia and Alzheimer's disease. a7 is also expressed in non-neuronal cells, particularly immune cells, where it plays a role in immunity, inflammation, and neuroprotection. Thus, a7 potentiation has emerged as a therapeutic strategy for several neurologic and inflammatory disorders. With unique activation properties, the receptor is a sensitive drug target carrying different potential binding sites for chemical modulators, particularly agonists and positive allosteric modulators. Although macroscopic and singlechannel recordings have provided significant information about the underlying molecular mechanisms and binding sites of modulatory compounds, we know just the tip of the iceberg. Further concerted efforts are necessary to effectively exploit a7 as a drug target for each pathologic situation. In this article, we focus mainly on the molecular basis of activation and drug modulation of a7, key pillars for rational drug design.

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“…It has been implicated in diverse biological functions and is an important target for therapeutics (1). ␣7nAChR mostly forms a homo-pentameric ligand-gated ion channel (pLGIC) that conducts calcium and other cations, though heteromeric ␣7␤2-nAChR has also been found in both heterologous expression systems and native neurons (16,17). Structures of the extracellular domain (ECD) and transmembrane domain (TMD) of ␣7nAChR have been determined separately by x-ray crystallography (18) and NMR (19), but the full-length human ␣7nAChR has not previously been obtained from any species in a form suitable for structure determination (20,21).…”

mentioning

confidence: 99%

Functional Human α7 Nicotinic Acetylcholine Receptor (nAChR) Generated from Escherichia coli

Tillman¹,

Alvarez²,

Reinert³

et al. 2016

Journal of Biological Chemistry

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Human Cys-loop receptors are important therapeutic targets. High-resolution structures are essential for rational drug design, but only a few are available due to difficulties in obtaining sufficient quantities of protein suitable for structural studies. Although expression of proteins in E. coli offers advantages of high yield, low cost, and fast turnover, this approach has not been thoroughly explored for full-length human Cys-loop receptors because of the conventional wisdom that E. coli lacks the specific chaperones and post-translational modifications potentially required for expression of human Cys-loop receptors. Here we report the successful production of full-length wild type human ␣7nAChR from E. coli. Chemically induced chaperones promote high expression levels of well-folded proteins. The choice of detergents, lipids, and ligands during purification determines the final protein quality. The purified ␣7nAChR not only forms pentamers as imaged by negativestain electron microscopy, but also retains pharmacological characteristics of native ␣7nAChR, including binding to bungarotoxin and positive allosteric modulators specific to ␣7nAChR. Moreover, the purified ␣7nAChR injected into Xenopus oocytes can be activated by acetylcholine, choline, and nicotine, inhibited by the channel blockers QX-222 and phencyclidine, and potentiated by the ␣7nAChR specific modulators PNU-120596 and TQS. The successful generation of functional human ␣7nAChR from E. coli opens a new avenue for producing mammalian Cys-loop receptors to facilitate structure-based rational drug design.Human Cys-loop receptors are promising therapeutic targets for various neurological disorders and diseases (1-4). Structure-based drug design for these receptors requires their high-resolution structures (5). Although Cys-loop receptors contain only four major receptor types, including nicotinic acetylcholine receptors (nAChRs), 2 serotonin 5-HT3 receptors, glycine receptors, and GABA A receptors, each receptor type often has multiple subtypes that form numerous functional distinct receptors. Among the human Cys-loop receptors, highresolution structures have been obtained for only the ␤3 GABA A and ␣3 glycine receptors (6, 7). Structures for other eukaryotic Cys-loop receptors include the mouse serotonin 5-HT3A receptor (8), the zebrafish ␣1 glycine receptor (9), the Caenorhabditis elegans GluCl (10, 11) and the muscle-type nicotinic acetylcholine receptor (nAChR) from Torpedo marmorota (12). The dichotomy between the small number of available structures and the relatively large receptor population in the superfamily indicates the technical difficulties for structural determination of these receptors. One of the greatest challenges for structural determination of Cys-loop receptors and similarly complex human membrane proteins is the production of a large quantity of well-folded functional proteins.The ␣7 nAChR (␣7nAChR) is one of the most abundant nAChR subtypes found in the brain (13,14). It is also expressed in a wide variety of non-neuronal tiss...

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Insights into Distinct Modulation of α7 and α7β2 Nicotinic Acetylcholine Receptors by the Volatile Anesthetic Isoflurane

Cited by 36 publications

References 54 publications

Allosteric modulation of nicotinic acetylcholine receptors

Allosteric modulation of nicotinic acetylcholine receptors

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

Functional Human α7 Nicotinic Acetylcholine Receptor (nAChR) Generated from Escherichia coli

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