Identification and Characterization of a G Protein-binding Cluster in α7 Nicotinic Acetylcholine Receptors

King, Justin R.; Nordman, Jacob C.; Bridges, Samuel P.; Lin, Mingkuan; Kabbani, Nadine

doi:10.1074/jbc.m115.647040

Cited by 99 publications

(136 citation statements)

References 48 publications

(110 reference statements)

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“…␣7 nAChR has been shown to modulate several signaling pathways, such as JAK2/STAT3/NF-B, PLC/ inositol 1,4,5-trisphosphate, and PI3K/Akt/Nrf-2 pathways, which in immune cells result in potent anti-inflammatory effects through inflammatory cytokine production inhibition and overexpression of hemooxigenase-1 (54,(57)(58)(59). Also, a direct coupling of ␣7 nAChR to G-protein has been recently described (60,61). Thus, our study opens doors to decipher in human NK cells the highly complex signaling pathways triggered by ␣7 nAChR and their association to different cell functions.…”

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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“…a7 binds both Ga and Gbg proteins through the M3-M4 loop and enables a downstream calcium signaling response that can persist beyond the expected time course of channel activation (Fig. 5) (Kabbani et al, 2013;King et al, 2015). Moreover, in lymphocyte T cells, mobilization of Ca 21 through the a7 channel is not necessarily required for the nicotine-induced release of Ca 21 from the internal stores (Razani-Boroujerdi et al, 2007).…”

Section: A7 Pharmacology and Ion Selectivitymentioning

confidence: 99%

“…The transient increase of calcium may also lead to a sustained calcium response by a calcium-induced calcium release (CICR) mechanism through IP 3 receptors. As a metabotropic receptor, a7 mediates intracellular signals by binding to Ga and Gbg proteins and several other partners (Kabbani et al, 2013;King et al, 2015). In immune cells, a7 has been shown to be involved in several intracellular pathways; although not yet fully deciphered mechanistically, these pathways lead to potent anti-inflammatory effects.…”

Section: A7 Channel Kineticsmentioning

confidence: 99%

“…2). Functional domains include the extracellular domain (ECD), which carries the agonist binding sites at subunit interfaces; the transmembrane domain (TMD), which contains the ion pore and the gate; and the intracellular domain (ICD), which contains determinants of channel conductance and sites for regulation and intracellular signaling (Paulo et al, 2009;Jones et al, 2010;King et al, 2015) (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

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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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“…1,11–13 The possibility of α7 nAChRs mediating metabotropic responses through direct coupling of the nicotinic receptor intracellular domain to G-proteins has been suggested based on mutational analysis of the intracellular domain M3M4 loop. 14–15 …”

Section: Introductionmentioning

confidence: 99%

Sulfonium as a Surrogate for Ammonium: A New α7 Nicotinic Acetylcholine Receptor Partial Agonist with Desensitizing Activity

et al. 2017

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Weak partial agonists that promote a desensitized state of the α7 nicotinic acetylcholine receptor (nAChR) have been associated with anti-inflammatory effects. Exemplar compounds feature a tertiary or quaternary ammonium group. We report the synthesis, structure, and electrophysiological evaluation of 1-ethyl-4-phenylthiomorpholin-1-ium triflate, a weak partial agonist with a sulfonium isostere of the ammonium pharmacophore. These results offer new insights in understanding nAChR-ligand interactions and provide a new chemical space to target the α7 nAChR.

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Identification and Characterization of a G Protein-binding Cluster in α7 Nicotinic Acetylcholine Receptors

Cited by 99 publications

References 48 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

Sulfonium as a Surrogate for Ammonium: A New α7 Nicotinic Acetylcholine Receptor Partial Agonist with Desensitizing Activity

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