title: The G-protein inhibitor, pertussis toxin, inhibits the secretion of brain-derived neurotrophic factor.
abstract: Secretion of neurotrophins is critical for the delivery of neurotrophic support. Brain-derived neurotrophic factor is targeted to a regulated secretory pathway in neurons as well as the neurosecretory AtT-20 cells. Here, we show that pertussis toxin, which inactivates Gi and Go G proteins, inhibits up to 50% of the regulated release of brain derived neurotrophic factor by AtT-20 cells. To determine whether pertussis toxin-sensitive G proteins may regulate brain-derived neurotrophic factor release in vivo, the effect of intraocular pertussis toxin was assessed on the isthmo-optic nucleus in the developing chick visual system. The isthmo-optic nucleus projects axons from the midbrain to innervate retinal amacrine cells and depends on target-derived brain-derived neurotrophic factor between embryonic days 13 and 17 (E13-17). During this period approximately 50% of isthmo-optic neurons are eliminated by programmed cell death. Intraocular pertussis toxin administered at E13 increased cell death of isthmo-optic neurons by 42%, whereas injections at E19 had no effect. Co-injection of brain-derived neurotrophic factor with pertussis toxin rescued approximately 50% of isthmo-optic neurons from enhanced cell death, although overall retinal brain derived neurotrophic factor protein levels were unaffected by pertussis toxin. Retrograde transport of exogenous 125I-labeled brain derived neurotrophic factor from the retina to the midbrain was increased by co-administration of pertussis toxin, possibly owing to diminished competition from endogenously released brain-derived neurotrophic factors for the receptors that mediate retrograde axonal transport. These data suggest that the release of a major fraction of brain-derived neurotrophic factor in the secretory pathway in vitro and in vivo is regulated by the activity of pertussis toxin-sensitive G proteins.
authors.affiliation: Department of Physiology and Biophysics, Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Gunther
authors.forename: C S
authors.initials: CS
authors.lastname: von Bartheld
authors.forename: L J
authors.initials: LJ
authors.lastname: Goodman
authors.forename: J E
authors.initials: JE
authors.lastname: Johnson
authors.forename: M
authors.initials: M
authors.lastname: Bothwell
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002642:Chick Embryo; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009994:Osmolar Concentration; D037342:Pertussis Toxin; D011189:Potassium Chloride / Q000494:pharmacology; D012160:Retina / Q000502:physiology; D014018:Tissue Distribution; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*; D014795:Visual Pathways / Q000166:cytology / Q000187:drug effects / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010566:Virulence Factors, Bordetella; D011189:Potassium Chloride; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; C498819:GNAI3 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C417708:Gnai3 protein, mouse; D020962:Heterotrimeric GTP-Binding Proteins