title: Secretion of brain-derived neurotrophic factor from PC12 cells in response to oxidative stress requires autocrine dopamine signaling.
abstract: Expression of brain-derived neurotrophic factor (BDNF) is sensitive to changes in oxygen availability, suggesting that BDNF may be involved in adaptive responses to oxidative stress. However, it is unknown whether or not oxidative stress actually increases availability of BDNF by stimulating BDNF secretion. To approach this issue we examined BDNF release from PC12 cells, a well-established model of neurosecretion, in response to hypoxic stimuli. BDNF secretion from neuronally differentiated PC12 cells was strongly stimulated by exposure to intermittent hypoxia (IH). This response was inhibited by N-acetyl-l-cysteine, a potent scavenger of reactive oxygen species (ROS) and mimicked by exogenous ROS. IH-induced BDNF release requires activation of tetrodotoxin sensitive Na+ channels and Ca2+ influx through N- and L-type channels, as well as mobilization of internal Ca2+ stores. These results demonstrate that oxidative stress can stimulate BDNF release and that underlying mechanisms are similar to those previously described for activity-dependent BDNF secretion from neurons. Surprisingly, we also found that IH-induced secretion of BDNF was blocked by dopamine D2 receptor antagonists or by inhibition of dopamine synthesis with alpha-methyl-p-tyrosine. These data indicate that oxidative stress can stimulate BDNF release through an autocrine or paracrine loop that requires dopamine receptor activation.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Yuan
authors.forename: Nanduri R
authors.initials: NR
authors.lastname: Prabhakar
authors.forename: Mark
authors.initials: M
authors.lastname: Boswell
authors.forename: David M
authors.initials: DM
authors.lastname: Katz
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D001896:Boron Compounds / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002069:Butaclamol / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003620:Dantrolene / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009553:Nimodipine / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D016716:PC12 Cells; D011189:Potassium Chloride / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D013469:Sulpiride / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: D001896:Boron Compounds; D019208:Brain-Derived Neurotrophic Factor; D002121:Calcium Channel Blockers; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D002104:Cadmium; D002110:Caffeine; D009553:Nimodipine; D011189:Potassium Chloride; D019284:Thapsigargin; D013469:Sulpiride; D020932:Nerve Growth Factor; D020866:omega-Conotoxin GVIA; D002069:Butaclamol; D006861:Hydrogen Peroxide; C109986:2-aminoethoxydiphenyl borate; D003620:Dantrolene; D004298:Dopamine