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T Cells Express 7-Nicotinic Acetylcholine Receptor Subunits That Require a Functional TCR and Leukocyte-Specific Protein Tyrosine Kinase for Nicotine-Induced Ca²⁺ Response¹

Seddigheh Razani-Boroujerdi^*, R. Thomas Boyd, Martha I. Dávila-García, Jayashree S. Nandi^*, Neerad C. Mishra^*, Shashi P. Singh^*, Juan Carlos Pena-Philippides^*, Raymond Langley^* and Mohan L. Sopori^2,*

^* Immunology Division, Lovelace Respiratory Research Institute, Albuquerque, NM 87108; Department of Neuroscience, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210; and Department of Pharmacology, College of Medicine, Howard University, Washington, DC 20059

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 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 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 7-nAChR subunit mRNA by RNA interference reduced the nicotine-induced Ca²⁺ response, but unlike the neuronal receptor, -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 and 7-nAChR coimmunoprecipitated with anti-CD3 or anti-7-nAChR Abs. These results suggest that in T cells, 7-nAChR, despite its close sequence homology with neuronal 7-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the National Institutes of Health (RO1 DA017003, R01 DA04208-15, and RO1DA04208).

² Address correspondence and reprint requests to Dr. Mohan L. Sopori, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108. E-mail address: msopori{at}lrri.org

³ Abbreviations used in this paper: nAChR, nicotinic acetylcholine receptor; -BTX, -bungarotoxin; MLA, methyllycaconitine; [Ca²⁺]_i, intracellular calcium; PTK, protein tyrosine kinase; WT, wild type; hT, human T cell; [³H]EB, [³H]epibatidine; Lck, leukocyte-specific tyrosine kinase; siRNA, small interfering RNA.

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