title: Autocrine endocannabinoid signaling through CB1 receptors potentiates OX1 orexin receptor signaling.
abstract: It has been proposed that OX(1) orexin receptors and CB(1) cannabinoid receptors can form heteromeric complexes, which affect the trafficking of OX(1) receptors and potentiate OX(1) receptor signaling to extracellular signal-regulated kinase (ERK). We have recently shown that OX(1) receptor activity releases high levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), suggesting an alternative route for OX(1)-CB(1) 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 OX(1) receptor-expressing cells acted as a potent paracrine messenger stimulating ERK activity in neighboring CB(1) receptor-expressing cells. When OX(1) and CB(1) receptors were expressed in the same cells, OX(1) stimulation-induced ERK phosphorylation and activity were strongly potentiated. The potentiation but not the OX(1) response as such was fully abolished by specific inhibition of CB(1) receptors or the enzyme responsible for 2-AG generation, diacylglycerol lipase (DAGL). Although the results do not exclude the previously proposed OX(1)-CB(1) heteromerization, they nevertheless unequivocally identify DAGL-dependent 2-AG generation as the pivotal determinant of the OX(1)-CB(1) synergism and thus suggest a functional rather than a molecular interaction of OX(1) and CB(1) receptors.
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Jäntti
authors.forename: Jaana
authors.initials: J
authors.lastname: Putula
authors.forename: Pauli M
authors.initials: PM
authors.lastname: Turunen
authors.forename: Johnny
authors.initials: J
authors.lastname: Näsman
authors.forename: Sami
authors.initials: S
authors.lastname: Reijonen
authors.forename: Christer
authors.initials: C
authors.lastname: Lindqvist
authors.forename: Jyrki P
authors.initials: JP
authors.lastname: Kukkonen
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D019898:Autocrine Communication; D016466:CHO Cells; D006224:Cricetinae; D063388:Endocannabinoids / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D006801:Humans; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D064446:Orexin Receptors; D010766:Phosphorylation / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D064446:Orexin Receptors; D043884:Receptor, Cannabinoid, CB1; D043643:Receptor, Muscarinic M1; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C094503:glyceryl 2-arachidonate; D048049:Extracellular Signal-Regulated MAP Kinases; D008071:Lipoprotein Lipase