PT - JOURNAL ARTICLE AU - Maria H Jantti AU - Jaana Putula AU - Pauli M Turunen AU - Johnny Nasman AU - Sami Reijonen AU - Christer Lindqvist AU - Jyrki P Kukkonen TI - Autocrine Endocannabinoid Signaling Through CB<sub>1</sub> Receptors Potentiates OX<sub>1</sub> Orexin Receptor Signaling AID - 10.1124/mol.112.080523 DP - 2012 Jan 01 TA - Molecular Pharmacology PG - mol.112.080523 4099 - http://molpharm.aspetjournals.org/content/early/2012/12/11/mol.112.080523.short 4100 - http://molpharm.aspetjournals.org/content/early/2012/12/11/mol.112.080523.full AB - 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) (Turunen et al., Mol Pharmacol 82(2): 156-167) 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 a) CB1 receptors or b) the enzyme responsible for 2-AG generation, diacylglycerol lipase. Although the results do not exclude the previously proposed OX1-CB1 heteromerization, they nevertheless unequivocally identify diacylglycerol lipase-dependent 2-AG generation as the pivotal determinant of the OX1-CB1 synergism and thus suggest rather a functional than a molecular interaction of OX1 and CB1 receptors.