Regulation of calcium by delta9-tetrahydrocannabinol

Michigan State University, East Lansing MI

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Abstract

DESCRIPTION (provided by applicant): Previous studies from this and other laboratories have demonstrated that delta9-tetrahydrocannabinol (delta9-THC), the primary psychoactive constituent in marijuana, can inhibit the expression of interleukin (IL)-2 by activated T cells. However, it remains unclear what role the cannabinoid receptors play in the regulation of IL-2 production by cannabinoids. Here, experiments were performed in murine splenic T cells or human T cell lines, HPB-ALL and Jurkat E6-1. The splenic T cells express both CB1 and CB2 receptor transcripts whereas the human T cells only express CB2 transcripts. Moreover, while HPB-ALL cells express normal CB2 receptors, the Jurkat E6-1 cells express dysfunctional CB2 receptors. Preliminary data using these cell models suggest that delta9-THC may inhibit IL-2 production via a premature rise in intracellular calcium ([Ca2+]i) in a cannabinoid receptor dependent manner. This research will be further pursued with the hypothesis that the inhibition of interleukin-2 expression by delta9-THC involves cannabinoid receptor-dependent elevation of [Ca((]i activation of calcium-dependent enzymes, protein kinase C (PKC) and calcium-dependent calmodulin kinase II (CaMKII), and modulation of nuclear factor of activated T cells (NFAT) activation. Future studies will be performed in the splenic T cells or HPB-ALL cells with three specific aims (SA). SA1) Investigation of the mechanism of [Ca2+]i elevation by ((-THC. SA2) Characterization of the effect of delta9-THC on PKC and CaMKII activation. SA3) Examination of the effect of delta9-THC-mediated elevation in [Ca2+]i on NFAT activation and IL-2 expression.