title: Cannabinoid receptor 1 modulates the autophagic flux independent of mTOR- and BECLIN1-complex.
abstract: Cannabinoid Receptor 1 (CB1) has been initially described as the receptor for Delta-9-Tetrahydrocannabinol in the central nervous system (CNS), mediating retrograde synaptic signaling of the endocannabinoid system. Beside its expression in various CNS regions, CB1 is ubiquituous in peripheral tissues, where it mediates, among other activities, the cell's energy homeostasis. We sought to examine the role of CB1 in the context of the evolutionarily conserved autophagic machinery, a main constituent of the regulation of the intracellular energy status. Manipulating CB1 by siRNA knockdown in mammalian cells caused an elevated autophagic flux, while the expression of autophagy-related genes remained unaltered. Pharmacological inhibition of CB1 activity using Rimonabant likewise caused an elevated autophagic flux, which was independent of the mammalian target of rapamycin complex 1, a major switch in the control of canonical autophagy. In addition, knocking down coiled-coil myosin-like BCL2-interacting protein 1, the key-protein of the second canonical autophagy control complex, was insufficient to reduce the elevated autophagic flux induced by Rimonabant. Interestingly, lysosomal activity is not altered, suggesting a specific effect of CB1 on the regulation of autophagic flux. We conclude that CB1 activity affects the autophagic flux independently of the two major canonic regulation complexes controlling autophagic vesicle formation. Regulation of the autophagic flux in certain physiological situations such as an imbalance of nutrient supply as well as in pathological stages is of major importance for neuronal and non-neuronal cells. CB1 (Cannabinoid receptor 1) affects the metabolism of cells directly. In this study, we provide evidence that CB1 signaling has a direct influence on autophagy which might help the cell to find the right adjustment to different metabolic states and CB1 activity exerts its modulatory action independent of the canonical mTOR- and BECLIN1-complexes regulating autophagy.
authors: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
authors: Christof
authors: C
authors: Hiebel
authors: Tanja
authors: T
authors: Kromm
authors: Marcel
authors: M
authors: Stark
authors: Christian
authors: C
authors: Behl
mesh_terms: D000227:Adenine Nucleotides / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071186:Beclin-1; D048588:Benzoxazines / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000227:Adenine Nucleotides; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; D004791:Enzyme Inhibitors; D018942:Macrolides; D008565:Membrane Proteins; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C040929:bafilomycin A1; D058570:TOR Serine-Threonine Kinases; D000077285:Rimonabant
keywords: CB1; GPCR; autophagy; non-canonical; peripheral