Cannabinoid receptor-mediated regulation of intracellular calcium by -tetrahydrocannabinol in T cells

Cannabinoids exhibit broad, immune, modulating activity by targeting many cell types within the immune system, including T cells, which exhibit sensitivity, as evidenced by altered activation, proliferation, and cytokine expression. As a result of the critical role calcium plays in T cell function coupled with previous findings demonstrating disruption of the calcium-regulated transcription factor, nuclear factor of activated T cells, by cannabinoid treatment, the objective of the present investigation was to perform an initial characterization of the role of the cannabinoid receptors in the regulation of the intracellular calcium concentration ([Ca ]i) by -tetrahydrocannabinol ( -THC) in T lymphocytes. Here, we demonstrate that -THC robustly elevates [Ca ]i in purified, murine, splenic T cells and in the human peripheral blood acute lymphoid leukemia (HPB-ALL) human T cell line but only minimally elevates [Ca ]i in Jurkat E6-1 (dysfunctional cannabinoid receptor 2-expressing) human T cells. Removal of extracellular calcium severely attenuated the -THC-mediated rise in [Ca ]i in murine, splenic T cells and HPB-ALL cells. Pretreatment with cannabinoid receptor antagonists, SR144528 and/or SR141716A, led to an attenuation of -THC-mediated elevation in [Ca ]i in splenic T cells and HPB-ALL cells but not in Jurkat E6-1 cells. Furthermore, pretreatment of HPBALL cells with SR144528 antagonized the small rise in [Ca ]i elicited by -THC in the absence of extracellular calcium. These findings suggest that -THC induces an influx of extracellular calcium in T cells in a cannabinoid receptor-dependent manner. J. Leukoc. Biol. 75: 000–000; 2004.