Nicotine-induced Ca2+ signaling and down-regulation of nicotinic acetylcholine receptor subunit expression in the CEM human leukemic T-cell line

Kimura, Reika; Ushiyama, Naoki; Fujii, Takeshi; Kawashima, Koichiro

doi:10.1016/s0024-3205(03)00077-8

Cited by 64 publications

(34 citation statements)

References 7 publications

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“…Nicotine dose-dependently down-regulates expression of mRNAs encoding all the nAChR subunits tested: expression of the α6 and α7 subunits was downregulated within the first week, while expression of the α3 and α5 subunits declined gradually throughout the 8-week experimental period (37). Consistent with those finings, levels of expression of nAChR α7-and α5-subunit mRNAs are significantly diminished in peripheral MNLs from smokers, as compared to those from nonsmokers (Fig.…”

Section: +supporting

confidence: 75%

“…In addition, epibatidine, a selective agonist for human α3β2, α3β4, and α7 nAChRs, and α-BTX each significantly reduced the numbers of epibatidine-responsive cells (37). These findings indicate that nAChR α7 subunit-mediated Ca 2+ -signaling pathways are operating in T-lymphocytes and that they are strongly dependent on an influx of extracellular Ca…”

Section: +mentioning

confidence: 77%

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Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of an Independent, Non-neuronal Cholinergic System in Lymphocytes and Its Clinical Significance in Immunotherapy

Fujii

Takada‐Takatori

Kawashima³

2008

J Pharmacol Sci

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106

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Abstract. Lymphocytes possess all the components required to constitute an independent, non-neuronal cholinergic system. These include acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). ACh modifies T and B cell function via both mAChR-and nAChRmediated pathways. Stimulation of lymphocytes with the T cell activator phytohemagglutinin, protein kinase C activator phorbol ester, or cell surface molecules enhances the synthesis and release of ACh and up-regulates ChAT and / or M 5 mAChR gene expression. Furthermore, animal models of immune disorders exhibit abnormal lymphocytic cholinergic activity. The cholesterollowering drug simvastatin attenuates the lymphocytic cholinergic activity of T cells by inhibiting LFA-1 signaling in a manner independent of its cholesterol-lowering activity. This suggests that simvastatin exerts its immunosuppressive effects in part by modifying lymphocytic cholinergic activity. Nicotine, an active ingredient of tobacco, ameliorates ulcerative colitis but exacerbates Crohn's disease. Expression of mRNAs encoding the nAChR α7 and α5 subunits are significantly diminished in peripheral mononuclear leukocytes from smokers, as compared with those from nonsmokers. In addition, long-term exposure of lymphocytes to nicotine reduces intracellular Ca 2+ signaling via α7 nAChR-mediated pathways. In fact, studies of humoral antibody production in M 1 / M 5 mAChR-deficient and α7 nAChR-deficient animals revealed the role of lymphocytic cholinergic activity in the regulation of immune function. These results provide clues to understanding the mechanisms underlying immune system regulation and could serve as the basis for the development of new immunomodulatory drugs.

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Section: +supporting

confidence: 75%

Section: +mentioning

confidence: 77%

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of an Independent, Non-neuronal Cholinergic System in Lymphocytes and Its Clinical Significance in Immunotherapy

Fujii

Takada‐Takatori

Kawashima³

2008

J Pharmacol Sci

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106

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“…In vivo, nicotine regulates T cell function by direct interaction with T cells and indirectly through neuroimmune interactions (18,24). RT-PCR analysis suggests the expression of ␣7-like nAChR nucleotide sequences in T cells (25)(26)(27)(28)(29), but their structure and function have not been clearly identified. Exposure of T cells to nicotine stimulates protein tyrosine kinase (PTK) activities and raises the [Ca 2ϩ ] i concentration (18), indicating that T cells respond directly to nicotine.…”

Section: T He Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

“…Exposure of T cells to nicotine stimulates protein tyrosine kinase (PTK) activities and raises the [Ca 2ϩ ] i concentration (18), indicating that T cells respond directly to nicotine. It is generally assumed that nAChRs on all cell types, including those on nonneuronal cells, are cation channels (28,30), but no electrophysiological evidence supports the presence of nicotine-sensitive, ligand-gated cation channels on T cells. Recent evidence suggests that ␣7-nAChRs on some neuronal cells fail to raise nicotine-induced [Ca 2ϩ ] i (31), and in astrocytes the nicotine-induced rise in [Ca 2ϩ ] i is amplified by Ca 2ϩ -induced Ca 2ϩ influx (32,33).…”

Section: T He Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

T Cells Express α7-Nicotinic Acetylcholine Receptor Subunits That Require a Functional TCR and Leukocyte-Specific Protein Tyrosine Kinase for Nicotine-Induced Ca2+ Response

Razani‐Boroujerdi

Boyd

Dávila‐García

et al. 2007

The Journal of Immunology

157

132

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Acute and chronic effects of nicotine on the immune system are usually opposite; acute treatment stimulates while chronic nicotine suppresses immune and inflammatory responses. Nicotine acutely raises intracellular calcium ([Ca2+]i) in T cells, but the mechanism of this response is unclear. Nicotinic acetylcholine receptors (nAChRs) are present on neuronal and non-neuronal cells, but while in neurons, nAChRs are cation channels that participate in neurotransmission; their structure and function in nonexcitable cells are not well-defined. In this communication, we present evidence that T cells express α7-nAChRs that are critical in increasing [Ca2+]i in response to nicotine. Cloning and sequencing of the receptor from human T cells showed a full-length transcript essentially identical to the neuronal α7-nAChR subunit (>99.6% homology). These receptors are up-regulated and tyrosine phosphorylated by treatment with nicotine, anti-TCR Abs, or Con A. Furthermore, knockdown of the α7-nAChR subunit mRNA by RNA interference reduced the nicotine-induced Ca2+ response, but unlike the neuronal receptor, α-bungarotoxin and methyllycaconitine not only failed to block, but also actually raised [Ca2+]i in T cells. The nicotine-induced release of Ca2+ from intracellular stores in T cells did not require extracellular Ca2+, but, similar to the TCR-mediated Ca2+ response, required activation of protein tyrosine kinases, a functional TCR/CD3 complex, and leukocyte-specific tyrosine kinase. Moreover, CD3ζ and α7-nAChR coimmunoprecipitated with anti-CD3ζ or anti-α7-nAChR Abs. These results suggest that in T cells, α7-nAChR, despite its close sequence homology with neuronal α7-nAChR, fails to form a ligand-gated Ca2+ channel, and that the nicotine-induced rise in [Ca2+]i in T cells requires functional TCR/CD3 and leukocyte-specific tyrosine kinase.

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“…A relatively high expression of CHRFAM7A in T-lymphocytes of the healthy individuals studied, as well as lack of expression of this gene in the same cells of ADNFLE patients, were not a result of contact with nicotine, since all individuals tested were non-smokers and never smoked. We took note of smoking as a factor since the study by Kimura et al [26] demonstrated that nicotine decreased the mRNA level of CHRFAM7A in a T-lymphocyte model cell line. We also excluded the effect of antiepileptic drug (AED), carbamazepine, on CHRFAM7A expression, since there was no expression of this gene in either the two patients who did not take this drug or in the proband who was treated with carbamazepine.…”

Section: B B Exon 6 Exonmentioning

confidence: 99%

Original article A transcript coding for a partially duplicated form of α7 nicotinic acetylcholine receptor is absent from the CD4 + T-lymphocytes of patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)

Różycka¹,

Dorszewska²,

Steinborn³

et al. 2013

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A Ag ga at ta a R Ro oz zy yc ck ka a 1 1 , , J Jo ol la an nt ta a D Do or rs sz ze ew ws sk ka a 2 2 , , B Ba ar rb ba ar ra a S St te ei in nb bo or rn n 3 3 , , B Ba ar rt to os sz z K Ke em mp pi is st ty y A b s t r a c t I In nt tr ro od du uc ct ti io on n: : It has been suggested that the homomer-forming α7 subunit (CHRNA7) of the neuronal nicotinic acetylcholine receptor (nAChR) is involved in the pathogenesis of common idiopathic generalized epilepsies (IGEs), whereas mutations of the gene coding for the α4 nAChR subunit (CHRNA4) are associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Several genes encoding nAChR subunits, including a partially duplicated isoform

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Nicotine-induced Ca2+ signaling and down-regulation of nicotinic acetylcholine receptor subunit expression in the CEM human leukemic T-cell line

Cited by 64 publications

References 7 publications

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of an Independent, Non-neuronal Cholinergic System in Lymphocytes and Its Clinical Significance in Immunotherapy

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of an Independent, Non-neuronal Cholinergic System in Lymphocytes and Its Clinical Significance in Immunotherapy

T Cells Express α7-Nicotinic Acetylcholine Receptor Subunits That Require a Functional TCR and Leukocyte-Specific Protein Tyrosine Kinase for Nicotine-Induced Ca2+ Response

Original article A transcript coding for a partially duplicated form of α7 nicotinic acetylcholine receptor is absent from the CD4 + T-lymphocytes of patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)

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