title: Role of mitochondrial activation in PACAP dependent neurite outgrowth.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) increases neurite outgrowth, although signaling via its receptor PACAP-specific receptor (PAC1R) has not been fully characterized. Because mitochondria also play an important role in neurite outgrowth, we examined whether mitochondria contribute to PACAP-mediated neurite outgrowth. When mouse primary hippocampal neurons and Neuro2a cells were exposed to PACAP, neurite outgrowth and the mitochondrial membrane potential increased in both cell types. These results were reproduced using the PAC1R-specific agonist maxadilan and the adenylate cyclase activator forskolin, whereas the protein kinase A inhibitor H89 and mitochondrial uncoupling agent carbonyl cyanide m-chlorophenyl hydrazone (CCCP) inhibited these effects. Expression levels of peroxisome proliferator-activated receptor γ coactivator 1α (Pgc1α), a master regulator of mitochondrial activation, and its downstream effectors, such as cytochrome C and cytochrome C oxidase subunit 4, increased in response to PACAP. Knocking down Pgc1α expression using small interfering RNA or treatment with CCCP significantly attenuated neurite outgrowth and reduced the mitochondrial membrane potential in PACAP-treated cells. These data suggest that mitochondrial activation plays a key role in PACAP-induced neurite outgrowth via a signaling pathway that includes PAC1R, PKA, and Pgc1α.
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagosima-shi, Kagoshima 890-8544, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kambe
authors.forename: Atsuro
authors.initials: A
authors.lastname: Miyata
mesh_terms: D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000196:embryology; D019476:Insect Proteins / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D016501:Neurites / Q000187:drug effects* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000819:agonists; D015290:Second Messenger Systems / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors
chemical_list: D019476:Insect Proteins; D007546:Isoquinolines; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C485290:Ppargc1a protein, mouse; D034741:RNA, Small Interfering; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D013449:Sulfonamides; D015534:Trans-Activators; D014157:Transcription Factors; C069147:maxadilan protein, insect; D005576:Colforsin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide