Allosteric modulation of nicotinic acetylcholine receptors

Chatzidaki, Anna; Millar, Neil S.

doi:10.1016/j.bcp.2015.07.028

Cited by 95 publications

(92 citation statements)

References 179 publications

(164 reference statements)

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“…Potentiation of ␣7 nAChR can be achieved by the use of agonists or PAMs, and both types of ligands emerge as potential therapeutic drugs (16,73,74). In particular, PAMs are of interest because they enhance ␣7 nAChR responses maintaining the temporal spatial characteristics of the endogenous activation, and they show higher specificity than agonists.…”

Section: Discussionmentioning

confidence: 99%

Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells

Zanetti

Ziblat

Torres

et al. 2016

Journal of Biological Chemistry

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The homomeric ␣7 nicotinic receptor (nAChR) is one of the most abundant nAChRs in the central nervous system where it contributes to cognition, attention, and working memory. ␣7 nAChR is also present in lymphocytes, dendritic cells (DCs), and macrophages and it is emerging as an important drug target for intervention in inflammation and sepsis. Natural killer (NK) cells display cytotoxic activity against susceptible target cells and modulate innate and adaptive immune responses through their interaction with DCs. We here show that human NK cells also express ␣7 nAChR. ␣7 nAChR mRNA is detected by RT-PCR and cell surface expression of ␣7 nAChR is detected by confocal microscopy and flow cytometry using ␣-bungarotoxin, a specific antagonist. Both mRNA and protein levels increase during NK stimulation with cytokines (IL-12, IL-18, and IL-15). Exposure of cytokine-stimulated NK cells to PNU-282987, a specific ␣7 nAChR agonist, increases intracellular calcium concentration ([Ca2؉

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Section: Discussionmentioning

confidence: 99%

Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells

Zanetti

Ziblat

Torres

et al. 2016

Journal of Biological Chemistry

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“…Thus, when analyzed at the molecular level, potentiation is more complex than initially believed. Moreover, PAMs showing macroscopic intermediate type I/II properties were proposed (Dunlop et al, 2009;Malysz et al, 2009;Dinklo et al, 2011;Sahdeo et al, 2014;Chatzidaki and Millar, 2015). Therefore, the classification of type I and type II appears to be an oversimplification resulting mainly from macroscopic observations, and a more thorough classification may be required.…”

Section: Modulatory Sites Pnu-120596mentioning

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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“…The muscle‐type nicotinic acetylcholine receptor (nAChR) is a target for diverse compounds, including steroid hormones, which act as noncompetitive modulators. Both the transmembrane and extra‐transmembrane locations are proposed as modulatory sites, which are distinct from that at which ACh acts as an agonist …”

Section: Introductionmentioning

confidence: 99%

Hydrocortisone inhibition of wild‐type and αD200Q nicotinic acetylcholine receptors

2018

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Short-term treatment with large doses of corticosteroids can result in acute weakness of muscles in processes that have not yet been fully characterized. Corticosteroids have been shown to exert direct inhibitory action on the muscle-type nicotinic acetylcholine receptor (AChR), and therefore can promote pharmacological muscle denervation. The mechanism of hydrocortisone (HC) blockage of AChR has not been fully established yet. It is uncommon for an electrically neutral molecule, for example, HC, to induce voltage-dependent changes in AChR kinetics. Our experiments aimed to determine the source of voltage-dependency in HC action. Wild-type (WT) and αD200Q receptors were transiently expressed in HEK293 cells. Recordings were performed in either the presence or absence of HC. We showed that the D-to-Q substitution is capable of suppressing the voltage dependency in the HC-induced block. We conclude that the distance between αD200 and the agonist-binding site depends on the membrane potential. The voltage-dependent changes of the αD200 position have not been considered yet. To our knowledge, the ability to induce voltage-dependency in blocker action has not been shown previously for an amino acid located outside the transmembrane portion of the receptor. Possible mechanisms of HC block (allosteric and knocking) in WT and αD200Q receptors are discussed.

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Allosteric modulation of nicotinic acetylcholine receptors

Cited by 95 publications

References 179 publications

Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells

Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells

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

Hydrocortisone inhibition of wild‐type and αD200Q nicotinic acetylcholine receptors

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