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Naunyn Schmiedebergs Arch Pharmacol ; 380(1): 67-77, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19255745

ABSTRACT

In human bronchial epithelial (16HBE14o(-)) cells, CB(1) and CB(2) cannabinoid receptors are present, and their activation by the endocannabinoid virodhamine and the synthetic non-selective receptor agonist CP55,940 inhibits adenylyl cyclase and cellular interleukin-8 release. Here, we analyzed changes in intracellular calcium ([Ca2+](i)) evoked by Delta(9)-tetrahydrocannabinol (Delta(9)-THC), CP55,940, and virodhamine in 16HBE14o(-) cells. Delta(9)-THC induced [Ca2+](i) increase and a large transient [Ca2+](i) mobilization, the latter probably reflecting store-depletion-driven capacitative Ca2+ entry (CCE). In contrast, CP55,940 induced a rather moderate Ca2+ influx and a sustained [Ca2+](i) mobilization. CP55,940-induced Ca2+ influx was inhibited by Ni2+, indicating CCE, possibly mediated by transient receptor potential channel TRPC1, the mRNA of which is expressed in 16HBE14o(-) cells. CP55,940-induced calcium alterations were mimicked by virodhamine concentrations below 30 microM. Interestingly, higher virodhamine induced an additional Ca2+ entry, insensitive to Ni2+, but sensitive to the TRPV1 antagonist capsazepine, the TRPV1-TRPV4 inhibitor ruthenium red, and the non-CCE (NCCE) inhibitors La3+ and Gd3+. Such pharmacological profile is supported by the presence of TRPV1, TRPV4, and TRPC6 mRNAs as well as TRPV1 and TRPC6 proteins in 16HBE14o(-) cells. Cannabinoid receptor antagonists increased virodhamine-induced Ca2+ entry. Virodhamine also enhanced arachidonic acid release, which was insensitive to cannabinoid receptor antagonism, but sensitive to the phospholipase A(2) inhibitor quinacrine, and to capsazepine. Arachidonic acid induced [Ca2+](i) increase similar to virodhamine. Collectively, these observations suggest that [Ca2+](i) alterations induced by Delta(9)-THC, CP55,940 and by low concentrations of virodhamine involve mobilization and subsequent CCE mechanisms, whereas such responses by high virodhamine concentrations involve NCCE pathways.


Subject(s)
Calcium/metabolism , Cannabinoid Receptor Modulators/pharmacology , Cannabinoids/pharmacology , Arachidonic Acid/metabolism , Arachidonic Acids/administration & dosage , Arachidonic Acids/pharmacology , Bronchi/cytology , Bronchi/drug effects , Bronchi/metabolism , Cannabinoid Receptor Modulators/administration & dosage , Cannabinoids/administration & dosage , Cell Line , Cyclohexanols/administration & dosage , Cyclohexanols/pharmacology , Dose-Response Relationship, Drug , Dronabinol/administration & dosage , Dronabinol/pharmacology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Humans , RNA, Messenger/metabolism , TRPC Cation Channels/metabolism
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