Cannabinoid receptor-mediated regulation of intracellular calcium by Δ9-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 ([Ca2+](i)) by Delta(9)-tetrahydrocannabinol (Delta(9)-TUC) in T lymphocytes. Here, we demonstrate that Delta(9)-THC robustly elevates [Ca2+](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 [Ca2+](i) in Jurkat E6-1 (dysfunctional cannabinoid receptor 2-expressing) human T cells. Removal of extracellular calcium severely attenuated the Delta(9)-THC-mediated rise in [Ca2+](i) in murine splenic T cells and HPB-ALL cells. Pretreatment with cannabinoid receptor antagonists, SR144528 and/or SR141716A, led to an attenuation of Delta(9)-THC-mediated elevation in [Ca2+](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 [Ca2+](i) elicited by Delta(9)-THC in the absence of extracellular calcium. These findings suggest that Delta(9)-THC induces an influx of extracellular calcium in resting T cells in a cannabinoid receptor-dependent manner.