T cells express alpha7-nicotinic acetylcholine receptor subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ response.
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 ([Ca(2+)](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 alpha7-nAChRs that are critical in increasing [Ca(2+)](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 alpha7-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 alpha7-nAChR subunit mRNA by RNA interference reduced the nicotine-induced Ca(2+) response, but unlike the neuronal receptor, alpha-bungarotoxin and methyllycaconitine not only failed to block, but also actually raised [Ca(2+)](i) in T cells. The nicotine-induced release of Ca(2+) from intracellular stores in T cells did not require extracellular Ca(2+), but, similar to the TCR-mediated Ca(2+) response, required activation of protein tyrosine kinases, a functional TCR/CD3 complex, and leukocyte-specific tyrosine kinase. Moreover, CD3zeta and alpha7-nAChR co-immunoprecipitated with anti-CD3zeta or anti-alpha7-nAChR Abs. These results suggest that in T cells, alpha7-nAChR, despite its close sequence homology with neuronal alpha7-nAChR, fails to form a ligand-gated Ca(2+) channel, and that the nicotine-induced rise in [Ca(2+)](i) in T cells requires functional TCR/CD3 and leukocyte-specific tyrosine kinase.
Razani-Boroujerdi
Seddigheh
S
Immunology Division, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA.
Boyd
R Thomas
RT
Dávila-García
Martha I
MI
Nandi
Jayashree S
JS
Mishra
Neerad C
NC
Singh
Shashi P
SP
Pena-Philippides
Juan Carlos
JC
Langley
Raymond
R
Sopori
Mohan L
ML
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology; D002038:Bungarotoxins / Q000494:pharmacology; D017252:CD3 Complex / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D019169:Jurkat Cells; D007962:Leukocytes / Q000201:enzymology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; D017252:CD3 Complex; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D011725:Pyridines; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D009538:Nicotine; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; C082748:epibatidine; D002118:Calcium; D000157:Aconitine