Published online before print October 21, 2005
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Article |
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
@ To whom correspondence should be addressed. 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 sarco-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 1-{
-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole 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, 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:
cannabinoid • 9-THC • TRP channel • SOC channel • store depletion • OAG
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