Published online before print February 13, 2004

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(Journal of Leukocyte Biology. 2004;75:884-892.)
© 2004 by Society for Leukocyte Biology

Cannabinoid receptor-mediated regulation of intracellular calcium by ⁹-tetrahydrocannabinol in resting T cells

Gautham K. Rao^*,,, Wei Zhang^*, and Norbert E. Kaminski^*,,,1

^* Department of Pharmacology and Toxicology,
National Food Safety and Toxicology Center, and
Center for Integrative Toxicology, Michigan State University, East Lansing

¹Correspondence: Department of Pharmacology and Toxicology, 315 National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824. E-mail: kamins11{at}msu.edu

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 ⁹-tetrahydrocannabinol (⁹-THC) in T lymphocytes. Here, we demonstrate that 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 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 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 ⁹-THC in the absence of extracellular calcium. These findings suggest that ⁹-THC induces an influx of extracellular calcium in resting T cells in a cannabinoid receptor-dependent manner.

Key Words: immune system • CB2 • CP55, 940 • CB1 • SR141716A • SR144528

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