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Cannabinoid-mediated elevation of intracellular calcium: a structure-activity relationship.
J Pharmacol Exp Ther. 2006 May; 317(2):820-9.JP

Abstract

This laboratory has reported previously that Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabinol (CBN) robustly elevate intracellular calcium ([Ca(2+)](i)) in resting human and murine T cells, whereas CP55,940 [5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol], a high-affinity ligand for CB1 and CB2, does not. In light of our previous studies, the objective of the present investigation was to examine the ability of various cannabinoid compounds to elevate [Ca(2+)](i) in the CB2 receptor-expressing human peripheral blood acute lymphoid leukemia T cell line and the dependence of structural similarity to Delta(9)-THC therein. The present studies demonstrate that CBN and HU-210 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol], both tricyclic and in that respect structurally similar to Delta(9)-THC, elevate [Ca(2+)](i). The [Ca(2+)](i) elevation elicited by both CBN and HU-210 was attenuated upon removal of extracellular calcium and upon pretreatment with SK&F96365 [1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole], an inhibitor of receptor-operated cation channels. In addition, pretreatment with either CB1 or CB2 receptor antagonists attenuated the CBN- and HU-210-mediated [Ca(2+)](i) elevation. Further investigation of the dependence of Delta(9)-THC, CBN, and HU-210 on cannabinoid receptors using splenocytes from wild-type and CB1(-/-)/CB2(-/-) mice showed that the [Ca(2+)](i) elevation elicited by all three tricyclic cannabinoids was independent of CB1 and CB2. Moreover, both the CB1 and CB2 receptor antagonists attenuated that rise in [Ca(2+)](i) elicited by the tricyclic cannabinoids in the wild-type and CB1(-/-)/CB2(-/-) mouse splenocytes. Taken together, the present results demonstrate that classic tricyclic cannabinoids with structural similarity to Delta(9)-THC elicit a robust influx of calcium in T cells putatively through receptor-operated cation channels in a manner sensitive to the cannabinoid receptor antagonists, but independent of the CB1 and CB2 receptors.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Center for Integrative Toxicology, 315 Food Safety Building, Michigan State University, East Lansing, MI 48824-1317, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16436496

Citation

Rao, Gautham K., and Norbert E. Kaminski. "Cannabinoid-mediated Elevation of Intracellular Calcium: a Structure-activity Relationship." The Journal of Pharmacology and Experimental Therapeutics, vol. 317, no. 2, 2006, pp. 820-9.
Rao GK, Kaminski NE. Cannabinoid-mediated elevation of intracellular calcium: a structure-activity relationship. J Pharmacol Exp Ther. 2006;317(2):820-9.
Rao, G. K., & Kaminski, N. E. (2006). Cannabinoid-mediated elevation of intracellular calcium: a structure-activity relationship. The Journal of Pharmacology and Experimental Therapeutics, 317(2), 820-9.
Rao GK, Kaminski NE. Cannabinoid-mediated Elevation of Intracellular Calcium: a Structure-activity Relationship. J Pharmacol Exp Ther. 2006;317(2):820-9. PubMed PMID: 16436496.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabinoid-mediated elevation of intracellular calcium: a structure-activity relationship. AU - Rao,Gautham K, AU - Kaminski,Norbert E, Y1 - 2006/01/25/ PY - 2006/1/27/pubmed PY - 2006/6/10/medline PY - 2006/1/27/entrez SP - 820 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 317 IS - 2 N2 - This laboratory has reported previously that Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabinol (CBN) robustly elevate intracellular calcium ([Ca(2+)](i)) in resting human and murine T cells, whereas CP55,940 [5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol], a high-affinity ligand for CB1 and CB2, does not. In light of our previous studies, the objective of the present investigation was to examine the ability of various cannabinoid compounds to elevate [Ca(2+)](i) in the CB2 receptor-expressing human peripheral blood acute lymphoid leukemia T cell line and the dependence of structural similarity to Delta(9)-THC therein. The present studies demonstrate that CBN and HU-210 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol], both tricyclic and in that respect structurally similar to Delta(9)-THC, elevate [Ca(2+)](i). The [Ca(2+)](i) elevation elicited by both CBN and HU-210 was attenuated upon removal of extracellular calcium and upon pretreatment with SK&F96365 [1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole], an inhibitor of receptor-operated cation channels. In addition, pretreatment with either CB1 or CB2 receptor antagonists attenuated the CBN- and HU-210-mediated [Ca(2+)](i) elevation. Further investigation of the dependence of Delta(9)-THC, CBN, and HU-210 on cannabinoid receptors using splenocytes from wild-type and CB1(-/-)/CB2(-/-) mice showed that the [Ca(2+)](i) elevation elicited by all three tricyclic cannabinoids was independent of CB1 and CB2. Moreover, both the CB1 and CB2 receptor antagonists attenuated that rise in [Ca(2+)](i) elicited by the tricyclic cannabinoids in the wild-type and CB1(-/-)/CB2(-/-) mouse splenocytes. Taken together, the present results demonstrate that classic tricyclic cannabinoids with structural similarity to Delta(9)-THC elicit a robust influx of calcium in T cells putatively through receptor-operated cation channels in a manner sensitive to the cannabinoid receptor antagonists, but independent of the CB1 and CB2 receptors. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16436496/Cannabinoid_mediated_elevation_of_intracellular_calcium:_a_structure_activity_relationship_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16436496 DB - PRIME DP - Unbound Medicine ER -