Cannabinoid receptor‐mediated regulation of intracellular calcium by Δ 9 ‐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 2+ ] i ) by Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC) in T lymphocytes. Here, we demonstrate that Δ 9 ‐THC robustly elevates [Ca 2+ ] 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 2+ ] i in Jurkat E6‐1 (dysfunctional cannabinoid receptor 2‐expressing) human T cells. Removal of extracellular calcium severely attenuated the Δ 9 ‐THC‐mediated rise in [Ca 2+ ] i in murine splenic T cells and HPB‐ALL cells. Pretreatment with cannabinoid receptor antagonists, SR144528 and/or SR141716A, led to an attenuation of Δ 9 ‐THC‐mediated elevation in [Ca 2+ ] 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 2+ ] i elicited by Δ 9 ‐THC in the absence of extracellular calcium. These findings suggest that Δ 9 ‐THC induces an influx of extracellular calcium in resting T cells in a cannabinoid receptor‐dependent manner.