T cells express α7-nicotinic acetylcholine receptor Subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ response
T cells express α7-nicotinic acetylcholine receptor Subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ response
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DOI：
10.4049/jimmunol.179.5.2889
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Sopori, Mohan L.
中科院分区：
文献类型：
--
作者：
Razani-Boroujerdi, Seddigheh;Boyd, R. Thomas;Sopori, Mohan L.
尼古丁对免疫系统的急性和慢性影响通常是相反的;急性治疗刺激而慢性尼古丁抑制免疫和炎症反应。尼古丁可使T细胞内钙离子浓度（[Ca 2 +]（i））急剧升高，但这种反应的机制尚不清楚。烟碱型乙酰胆碱受体（nAChR）存在于神经元和非神经元细胞上，但在神经元中，nAChR是参与神经传递的阳离子通道;它们在非兴奋细胞中的结构和功能尚未明确。在这篇文章中，我们提出了T细胞表达α 7-nAChR的证据，这些证据在响应尼古丁时增加[Ca 2 +]i方面至关重要。从人T细胞中克隆和测序的受体显示全长转录基本上相同的神经元α 7-nAChR亚基（>99.6%同源性）。这些受体通过尼古丁、抗TCR抗体或Con A处理而上调并酪氨酸磷酸化。此外，通过RNA干扰敲低α 7-nAChR亚基mRNA降低了尼古丁诱导的Ca 2+反应，但与神经元受体不同，α-银环蛇毒素和methyllycaconitine不仅未能阻断，而且实际上还提高了T细胞中的[Ca 2 +]i。尼古丁诱导的T细胞胞内钙释放不需要细胞外钙，但与TCR介导的钙反应类似，需要激活蛋白酪氨酸激酶、功能性TCR/CD 3复合物和白细胞特异性酪氨酸激酶。此外，CD 3 zeta和α 7-nAChR与抗CD 3 zeta或抗α 7-nAChR Ab共免疫沉淀。这些结果表明，在T细胞中，尽管α 7-nAChR与神经元α 7-nAChR具有密切的序列同源性，但不能形成配体门控的Ca（2+）通道，并且尼古丁诱导的T细胞中[Ca 2 +]（i）的升高需要功能性TCR/CD 3和白细胞特异性酪氨酸激酶。
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 alpha 7-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 alpha 7-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 alpha 7-nAChR subunit mRNA by RNA interference reduced the nicotine-induced Ca2+ response, but unlike the neuronal receptor, alpha-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, CD3 zeta and alpha 7-nAChR coimmunoprecipitated with anti-CD3 zeta or anti-alpha 7-nAChR Abs. These results suggest that in T cells, alpha 7-nAChR, despite its close sequence homology with neuronal alpha 7-nAChR, fails to form a ligand-gated Ca (2+) channel, and that the nicotine-induced rise in [Ca2+](i) in T cells requires functional TCR/CD3 and leukocyte-specific tyrosine kinase.