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Molecular Pharmacology

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Research ArticleArticle

Autocrine Endocannabinoid Signaling through CB1 Receptors Potentiates OX1 Orexin Receptor Signaling

Maria H. Jäntti, Jaana Putula, Pauli M. Turunen, Johnny Näsman, Sami Reijonen, Christer Lindqvist and Jyrki P. Kukkonen
Molecular Pharmacology March 2013, 83 (3) 621-632; DOI: https://doi.org/10.1124/mol.112.080523
Maria H. Jäntti
Biochemistry and Cell Biology, Department of Veterinary Biosciences (M.H.J., J.P., P.M.T., S.R., J.P.K.), and Physiology, Institute of Biomedicine (P.M.T.), University of Helsinki, Helsinki, Finland; and Biochemistry (J.N.) and Cell Biology (C.L.), Department of Biosciences, Åbo Akademi University, Turku, Finland
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Jaana Putula
Biochemistry and Cell Biology, Department of Veterinary Biosciences (M.H.J., J.P., P.M.T., S.R., J.P.K.), and Physiology, Institute of Biomedicine (P.M.T.), University of Helsinki, Helsinki, Finland; and Biochemistry (J.N.) and Cell Biology (C.L.), Department of Biosciences, Åbo Akademi University, Turku, Finland
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Pauli M. Turunen
Biochemistry and Cell Biology, Department of Veterinary Biosciences (M.H.J., J.P., P.M.T., S.R., J.P.K.), and Physiology, Institute of Biomedicine (P.M.T.), University of Helsinki, Helsinki, Finland; and Biochemistry (J.N.) and Cell Biology (C.L.), Department of Biosciences, Åbo Akademi University, Turku, Finland
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Johnny Näsman
Biochemistry and Cell Biology, Department of Veterinary Biosciences (M.H.J., J.P., P.M.T., S.R., J.P.K.), and Physiology, Institute of Biomedicine (P.M.T.), University of Helsinki, Helsinki, Finland; and Biochemistry (J.N.) and Cell Biology (C.L.), Department of Biosciences, Åbo Akademi University, Turku, Finland
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Sami Reijonen
Biochemistry and Cell Biology, Department of Veterinary Biosciences (M.H.J., J.P., P.M.T., S.R., J.P.K.), and Physiology, Institute of Biomedicine (P.M.T.), University of Helsinki, Helsinki, Finland; and Biochemistry (J.N.) and Cell Biology (C.L.), Department of Biosciences, Åbo Akademi University, Turku, Finland
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Christer Lindqvist
Biochemistry and Cell Biology, Department of Veterinary Biosciences (M.H.J., J.P., P.M.T., S.R., J.P.K.), and Physiology, Institute of Biomedicine (P.M.T.), University of Helsinki, Helsinki, Finland; and Biochemistry (J.N.) and Cell Biology (C.L.), Department of Biosciences, Åbo Akademi University, Turku, Finland
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Jyrki P. Kukkonen
Biochemistry and Cell Biology, Department of Veterinary Biosciences (M.H.J., J.P., P.M.T., S.R., J.P.K.), and Physiology, Institute of Biomedicine (P.M.T.), University of Helsinki, Helsinki, Finland; and Biochemistry (J.N.) and Cell Biology (C.L.), Department of Biosciences, Åbo Akademi University, Turku, Finland
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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.

  • dx.doi.org/10.1124/mol.112.080523.

  • ↵Embedded ImageThis 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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Molecular Pharmacology: 83 (3)
Molecular Pharmacology
Vol. 83, Issue 3
1 Mar 2013
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Research ArticleArticle

CB1 Receptor Signaling Potentiates OX1 Receptor Signaling

Maria H. Jäntti, Jaana Putula, Pauli M. Turunen, Johnny Näsman, Sami Reijonen, Christer Lindqvist and Jyrki P. Kukkonen
Molecular Pharmacology March 1, 2013, 83 (3) 621-632; DOI: https://doi.org/10.1124/mol.112.080523

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Research ArticleArticle

CB1 Receptor Signaling Potentiates OX1 Receptor Signaling

Maria H. Jäntti, Jaana Putula, Pauli M. Turunen, Johnny Näsman, Sami Reijonen, Christer Lindqvist and Jyrki P. Kukkonen
Molecular Pharmacology March 1, 2013, 83 (3) 621-632; DOI: https://doi.org/10.1124/mol.112.080523
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