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Published online before print October 21, 2005

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(Journal of Leukocyte Biology. 2006;79:202-213.)
© 2006 by Society for Leukocyte Biology

Induction of intracellular calcium elevation by ⁹-tetrahydrocannabinol in T cells involves TRPC1 channels

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

¹ Correspondence: Department of Pharmacology & Toxicology and Center for Integrative Toxicology, 315 Food Safety Building, Michigan State University, East Lansing, MI 48824-1317. E-mail: kamins11{at}msu.edu

We have reported previously that ⁹-tetrahydrocannabinol (⁹-THC) treatment of resting human and murine splenic T cells robustly elevated intracellular calcium ([Ca²⁺]_i). The objective of the present investigation was to examine the putative role of [Ca²⁺]_i store depletion and store-operated calcium (SOC) [¹ ] and receptor-operated cation (ROC) channels in the mechanism by which ⁹-THC increases [Ca²⁺]_i in the cannabinoid-2 receptor-expressing human peripheral blood-acute lymphoid leukemia (HPB-ALL) human T cell line. By using the smooth endoplasmic reticulum Ca²⁺-ATPase pump inhibitor, thapsigargin, and the ryanodine receptor antagonist, 8-bromo-cyclic adenosine diphosphate ribose, we demonstrate that the ⁹-THC-mediated elevation in [Ca²⁺]_i occurs independently of [Ca²⁺]_i store depletion. Furthermore, the ROC channel inhibitor, SK&F 96365 was more efficacious at attenuating the ⁹-THC-mediated elevation in [Ca²⁺]_i than SOC channel inhibitors, 2-aminoethoxydiphenyl borate and La³⁺. Recently, several members of the transient receptor potential canonical (TRPC) channel subfamily have been suggested to operate as SOC or ROC channels. In the present studies, treatment of HPB-ALL cells with 1-oleoyl-2-acetyl-sn-glycerol (OAG), a cell-permeant analog of diacylglycerol (DAG), which gates several members of the TRPC channel subfamily, rapidly elevated [Ca²⁺]_i, as well as prevented a subsequent, additive elevation in [Ca²⁺]_i by ⁹-THC, independent of protein kinase C. Reverse transcriptase-polymerase chain reaction analysis for TRPC1–7 showed that HPB-ALL cells express detectable mRNA levels of only TRPC1. Finally, small interference RNA knockdown of TRPC1 attenuated the ⁹-THC-mediated elevation of [Ca²⁺]_i. Collectively, these results suggest that ⁹-THC-induced elevation in [Ca²⁺]_i is attributable entirely to extracellular calcium influx, which is independent of [Ca²⁺]_i store depletion, and is mediated, at least partially, through the DAG-sensitive TRPC1 channels.

Key Words: Key Words: • cannabinoid • ⁹-THC • TRP channel • SOC channel • store depletion • OAG

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