Nitric oxide down-regulates brain-derived neurotrophic factor secretion in cultured hippocampal neurons.
The regulation of neurotrophin (NT) secretion is critical for many aspects of NT-mediated neuronal plasticity. Neurons release NTs by activity-regulated secretion pathways, initiated either by neurotransmitters and/or by existing NTs by a positive-feedback mechanism. This process depends on calcium release from intracellular stores. Little is known, however, about potential pathways that down-regulate NT secretion. Here we demonstrate that nitric oxide (NO) induces a rapid down-regulation of brain-derived neurotrophic factor (BDNF) secretion in cultured hippocampal neurons. Similar effects occur by activating a downstream target of intracellular NO, the soluble guanylyl cyclase, or by increasing the levels of its product, cGMP. Furthermore, down-regulation of BDNF secretion is mediated by cGMP-activated protein kinase G, which prevents calcium release from inositol 1,4,5-trisphosphate-sensitive stores. Our data indicate that the NO/cGMP/protein kinase G pathway represents a signaling mechanism by which neurons can rapidly down-regulate BDNF secretion and suggest that, in hippocampal neurons, NT secretion is finely tuned by both stimulatory and inhibitory signals.
Canossa
Marco
M
Department of Pharmacology, University of Bologna, via Irnerio 48, 40216 Bologna, Italy. marco@biofarm.unibo.it
Giordano
Emanuele
E
Cappello
Silvia
S
Guarnieri
Carlo
C
Ferri
Sergio
S
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats
D019208:Brain-Derived Neurotrophic Factor; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D009599:Nitroprusside; D009569:Nitric Oxide; C061872:FK 409; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP