T cells express alpha7-nicotinic acetylcholine receptor subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ response

J Immunol. 2007 Sep 1;179(5):2889-98. doi: 10.4049/jimmunol.179.5.2889.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aconitine / analogs & derivatives
  • Aconitine / pharmacology
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Bungarotoxins / pharmacology
  • CD3 Complex / metabolism
  • Calcium / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Humans
  • Immunoprecipitation
  • Jurkat Cells
  • Leukocytes / enzymology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism*
  • Neurons / metabolism
  • Nicotine / pharmacology*
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Pyridines / metabolism
  • Pyridines / pharmacology
  • RNA, Small Interfering / pharmacology
  • Rats
  • Receptors, Antigen, T-Cell / antagonists & inhibitors
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Nicotinic / drug effects
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • alpha7 Nicotinic Acetylcholine Receptor


  • Bridged Bicyclo Compounds, Heterocyclic
  • Bungarotoxins
  • CD3 Complex
  • Chrna7 protein, human
  • Chrna7 protein, rat
  • Pyridines
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • methyllycaconitine
  • Nicotine
  • Protein-Tyrosine Kinases
  • FYN protein, human
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Proto-Oncogene Proteins c-fyn
  • epibatidine
  • Calcium
  • Aconitine