title: Corticotropin-releasing hormone-mediated induction of intracellular signaling pathways and brain-derived neurotrophic factor expression is inhibited by the activation of the endocannabinoid system.
abstract: CRH receptor (CRHR) 1 and the cannabinoid receptor 1 (CB1) are both G protein-coupled receptors. Activation of CRHR1 leads to increases in cAMP production and phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In contrast, CB1 is negatively coupled to the cAMP signaling cascade. In this study, we analyzed a putative interaction between these two systems focusing on the regulation of the expression of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene. In situ hybridization revealed coexpression of CRHR1 and CB1 receptors in the granular layer of the cerebellum. Therefore, we analyzed the effects of CRH and the CB1 agonist WIN-55,212-2 on BDNF expression in primary cerebellar neurons from rats and mice. We observed that application of CRH for 48 h led to an increase in BDNF mRNA and protein levels. This effect was inhibited by WIN-55,212-2. At the level of intracellular signaling, short-term application of WIN-55,212-2 inhibited CRH-induced cAMP accumulation and CREB phosphorylation. Pharmacological analysis demonstrated that the CRHR1 antagonist R121919, the protein kinase A inhibitor H89, and the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester inhibited CRH-mediated BDNF expression. Moreover, depolarization-induced BDNF synthesis was also inhibited by long-term application of WIN-55,212-2 in wild-type mice but not in CB1-deficient mice. Thus, these data highlight an interaction between the CRH and the cannabinoid system in the regulation of BDNF expression by influencing cAMP and Ca2+ signaling pathways.
authors.affiliation: Department of Pathobiochemistry, Johannes Gutenberg University Mainz Medical School, 55099 Mainz, Germany.
authors.forename: Nadhim
authors.initials: N
authors.lastname: Bayatti
authors.forename: Heike
authors.initials: H
authors.lastname: Hermann
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Christian
authors.initials: C
authors.lastname: Behl
mesh_terms: D000818:Animals; D048588:Benzoxazines; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D063388:Endocannabinoids; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D017403:In Situ Hybridization; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D048588:Benzoxazines; D019208:Brain-Derived Neurotrophic Factor; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D017362:Cyclic AMP Response Element-Binding Protein; D063388:Endocannabinoids; D007546:Isoquinolines; D009025:Morpholines; D009281:Naphthalenes; D011743:Pyrimidines; C412383:R 121919; D012333:RNA, Messenger; D013449:Sulfonamides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium