PT - JOURNAL ARTICLE AU - Julie A. Przybyla AU - Val J. Watts TI - Ligand-Induced Regulation and Localization of Cannabinoid CB<sub>1</sub> and Dopamine D<sub>2L</sub> Receptor Heterodimers AID - 10.1124/jpet.109.162701 DP - 2010 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 710--719 VI - 332 IP - 3 4099 - http://jpet.aspetjournals.org/content/332/3/710.short 4100 - http://jpet.aspetjournals.org/content/332/3/710.full SO - J Pharmacol Exp Ther2010 Mar 01; 332 AB - The cannabinoid CB1 (CB1) and dopamine D2 (D2) receptors are coexpressed in the basal ganglia, an area of the brain involved in such processes as cognition, motor function, and emotional control. Several lines of evidence suggest that CB1 and D2 receptors may oligomerize, providing a unique pharmacology in vitro and in vivo. However, limited information exists on the regulation of CB1 and D2 receptor dimers. We used a novel technique, multicolor bimolecular fluorescence complementation (MBiFC) to examine the subcellular localization of CB1-D2L heterodimers as well as D2L-D2L homodimers in a neuronal cell model, Cath. a differentiated cells. MBiFC was then used to explore the effects of persistent ligand treatment on receptor dimerization at the plasma membrane and intracellularly. Persistent (20-h) agonist treatment resulted in increased formation of CB1-D2L heterodimers relative to the D2L-D2L homodimers. The effects of the D2 agonist quinpirole were restricted to the intracellular compartment and may reflect increased D2L receptor expression. In contrast, treatment with the CB1 receptor agonist (2)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55, 940) produced increases in both membrane and intracellular CB1-D2L heterodimers independently of alterations in CB1 receptor expression. The effects of CB1 receptor activation were attenuated by the CB1 antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM281) and were both time- and dose-dependent. The effects of CB1 activation were examined further by combining MBiFC with a constitutively active CB1 receptor mutant, CB1T210I. These studies demonstrated that the expression of CB1T210I increased intracellular CB1-D2L heterodimer formation. In summary, agonist-induced modulation of CB1-D2L oligomerization may have physiological implications in diseases such as Parkinson's disease and drug abuse.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics