Abstract
It has been proposed that OX1 orexin receptors and CB1 cannabinoid receptors can form heteromeric complexes, which affect the trafficking of OX1 receptors and potentiate OX1 receptor signaling to extracellular signal–regulated kinase (ERK). We have recently shown that OX1 receptor activity releases high levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), suggesting an alternative route for OX1-CB1 receptor interaction in signaling, for instance, in retrograde synaptic transmission. In the current study, we set out to investigate this possibility utilizing recombinant Chinese hamster ovary K1 cells. 2-AG released from OX1 receptor–expressing cells acted as a potent paracrine messenger stimulating ERK activity in neighboring CB1 receptor–expressing cells. When OX1 and CB1 receptors were expressed in the same cells, OX1 stimulation–induced ERK phosphorylation and activity were strongly potentiated. The potentiation but not the OX1 response as such was fully abolished by specific inhibition of CB1 receptors or the enzyme responsible for 2-AG generation, diacylglycerol lipase (DAGL). Although the results do not exclude the previously proposed OX1-CB1 heteromerization, they nevertheless unequivocally identify DAGL-dependent 2-AG generation as the pivotal determinant of the OX1-CB1 synergism and thus suggest a functional rather than a molecular interaction of OX1 and CB1 receptors.
Footnotes
This study was supported by the Academy of Finland; the Magnus Ehrnrooth Foundation; the University of Helsinki Research Funds; the Alfred Kordelin Foundation; the Biomedicum Helsinki Foundation; the Åbo Akademi Foundation; and the Research Foundation of the University of Helsinki. J.P. is supported by the FinPharma Doctoral Program.
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This article has supplemental material available at molpharm.aspetjournals.org.
- Received June 8, 2012.
- Accepted December 11, 2012.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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