Stoichiometry for α-bungarotoxin block of α7 acetylcholine receptors

daCosta, Corrie J.B.; Free, Chris R.; Sine, Steven M.

doi:10.1038/ncomms9057

Cited by 43 publications

(53 citation statements)

References 39 publications

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“…One should also bear in mind that the α7 nAChR has 5 orthosteric binding sites for agonists/competitive antagonists, and that radioligand analysis monitors the displacement of the αBgt from all of them. On the contrary, to block the α7 nAChR function in electrophysiology tests, one molecule of the antagonist is sufficient49. In accordance with earlier findings35, the binding parameters obtained in the present communication from electrophysiology experiments on the α7 nAChR expressed in Xenopus oocytes (Fig.…”

Section: Discussionsupporting

confidence: 93%

High-Affinity α-Conotoxin PnIA Analogs Designed on the Basis of the Protein Surface Topography Method

Kasheverov

Chugunov

Kudryavtsev

et al. 2016

Sci Rep

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Despite some success for small molecules, elucidating structure–function relationships for biologically active peptides — the ligands for various targets in the organism — remains a great challenge and calls for the development of novel approaches. Some of us recently proposed the Protein Surface Topography (PST) approach, which benefits from a simplified representation of biomolecules’ surface as projection maps, which enables the exposure of the structure–function dependencies. Here, we use PST to uncover the “activity pattern” in α-conotoxins — neuroactive peptides that effectively target nicotinic acetylcholine receptors (nAChRs). PST was applied in order to design several variants of the α-conotoxin PnIA, which were synthesized and thoroughly studied. Among the best was PnIA[R9, L10], which exhibits nanomolar affinity for the α7 nAChR, selectivity and a slow wash-out from this target. Importantly, these mutations could hardly be delineated by “standard” structure-based drug design. The proposed combination of PST with a set of experiments proved very efficient for the rational construction of new bioactive molecules.

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Section: Discussionsupporting

confidence: 93%

High-Affinity α-Conotoxin PnIA Analogs Designed on the Basis of the Protein Surface Topography Method

Kasheverov

Chugunov

Kudryavtsev

et al. 2016

Sci Rep

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“…(ii) Occupancy of a single site by α‐bungarotoxin is enough to prevent channel opening (daCosta et al . ). This finding indicates that α‐BTX binding produces a conformational arrest in which ACh occupancy of the other four sites cannot lead to activation.…”

Section: Introductionmentioning

confidence: 97%

Molecular function of α7 nicotinic receptors as drug targets

Bouzat

Lasala

Nielsen

et al. 2017

The Journal of Physiology

119

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Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels involved in many physiological and pathological processes. In vertebrates, there are seventeen different nAChR subunits that combine to yield a variety of receptors with different pharmacology, function, and localization. The homomeric α7 receptor is one of the most abundant nAChRs in the nervous system and it is also present in non-neuronal cells. It plays important roles in cognition, memory, pain, neuroprotection, and inflammation. Its diverse physiological actions and associated disorders have made of α7 an attractive novel target for drug modulation. Potentiation of the α7 receptor has emerged as a novel therapeutic strategy for several neurological diseases, such as Alzheimer's and Parkinson's diseases, and inflammatory disorders. In contrast, increased α7 activity has been associated with cancer cell proliferation. The presence of different drug target sites offers a great potential for α7 modulation in different pathological contexts. In particular, compounds that target allosteric sites offer significant advantages over orthosteric agonists due to higher selectivity and a broader spectrum of degrees and mechanisms of modulation. Heterologous expression of α7, together with chaperone proteins, combined with patch clamp recordings have provided important advances in our knowledge of the molecular basis of α7 responses and their potential modulation for pathological processes. This review gives a synthetic view of α7 and its molecular function, focusing on how its unique activation and desensitization features can be modified by pharmacological agents. This fundamental information offers insights into therapeutic strategies.

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“…The most efficacious PAM to date is PNU-120596, a type II PAM . This compound elicits significantly prolonged openings that appear grouped in bursts, which in turn coalesce into long activation periods of several seconds, referred to as clusters (daCosta et al, 2011(daCosta et al, , 2015Williams et al, 2011b; Pałczy nska et al, 2012; Andersen et al, 2016). However, the …”

Section: A7 Modulation As a Therapeutic Strategymentioning

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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Stoichiometry for α-bungarotoxin block of α7 acetylcholine receptors

Cited by 43 publications

References 39 publications

High-Affinity α-Conotoxin PnIA Analogs Designed on the Basis of the Protein Surface Topography Method

High-Affinity α-Conotoxin PnIA Analogs Designed on the Basis of the Protein Surface Topography Method

Molecular function of α7 nicotinic receptors as drug targets

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

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