Cannabinoid receptor-mediated regulation of intracellular calcium by -tetrahydrocannabinol in resting 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 (HPBALL) 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 -THCmediated elevation in [Ca ]i in splenic T cells and HPB-ALL cells but not in Jurkat E6-1 cells. Furthermore, pretreatment of HPB-ALL 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 resting T cells in a cannabinoid receptor-dependent manner. J. Leukoc. Biol. 75: 884–892; 2004.