The G-protein inhibitor, pertussis toxin, inhibits the secretion of brain-derived neurotrophic factor

Secretion of neurotrophins is critical for the delivery of neurotrophic sup port. Brain-derived neurotrophic factor is targeted to a regulated secretor y pathway in neurons as well as the neurosecretory AtT-20 cells. Here, we s how 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 fr om the midbrain to innervate retinal amacrine cells and depends on target-d erived brain-derived neurotrophic factor between embryonic days 13 and 17 ( E13-17). During this period approximately 50% of isthmo-optic neurons are e liminated by programmed cell death. Intraocular pertussis toxin administere d at E13 increased cell death of isthmo-optic neurons by 42%, whereas injec tions at E19 had no effect. Go-injection of brain-derived neurotrophic fact or with pertussis toxin rescued approximately 50% of isthmo-optic neurons f rom enhanced cell death, although overall retinal brain derived neurotrophi c factor protein levels were unaffected by pertussis toxin. Retrograde tran sport of exogenous I-125-labeled brain derived neurotrophic factor from the retina to the midbrain was increased by co-administration of pertussis tox in, possibly owing to diminished competition from endogenously released bra in-derived neurotrophic factors for the receptors that mediate retrograde a xonal transport. These data suggest that the release of a major fraction of brain-derived ne urotrophic factor in the secretory pathway in vitro and in vivo is regulate d by the activity of pertussis toxin-sensitive G proteins. (C) 2000 IBRO. P ublished by Elsevier Science Ltd. All rights reserved.