Endocannabinoids are conserved inhibitors of the Hedgehog pathway.
Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate in human and Drosophila lipoproteins and act directly on Smoothened at physiological concentrations to repress signaling in Drosophila and mammalian assays. Phytocannabinoids are also potent Smo inhibitors. These findings link organismal metabolism to local Hedgehog signaling and suggest previously unsuspected mechanisms for the physiological activities of cannabinoids.
Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3DY Cambridge, United Kingdom; and hk402@cam.ac.uk eaton@mpi-cbg.de.
Helena
H
Khaliullina
Max Planck Institute of Molecular Biology and Genetics, 01307 Dresden, Germany.
Mesut
M
Bilgin
Max Planck Institute of Molecular Biology and Genetics, 01307 Dresden, Germany.
Julio L
JL
Sampaio
Max Planck Institute of Molecular Biology and Genetics, 01307 Dresden, Germany.
Andrej
A
Shevchenko
Max Planck Institute of Molecular Biology and Genetics, 01307 Dresden, Germany hk402@cam.ac.uk eaton@mpi-cbg.de.
Suzanne
S
Eaton
D000494:Allosteric Regulation; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D004331:Drosophila melanogaster / Q000378:metabolism*; D063388:Endocannabinoids / Q000097:blood / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D060227:Imaginal Discs / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D015398:Signal Transduction; D014921:Wings, Animal / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D063388:Endocannabinoids; D053823:Hedgehog Proteins; D008079:Lipoproteins, VLDL; D000099252:Fatty Acid Amide Hydrolases
endocannabinoids; hedgehog; lipids; lipoproteins; smoothened