Pituitary Adenylyl Cyclase-Activating Polypeptide and Nerve Growth Factor Use the Proteasome to Rescue Nerve Growth Factor-Deprived Sympathetic Neurons Cultured From Chick Embryos
| Autor: | Jayant S. Kulkarni, Dmitry V. Leontiev, Taruna D. Wakade, Arun R. Wakade, Dennis A. Przywara |
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| Rok vydání: | 2002 |
| Předmět: |
Proteasome Endopeptidase Complex
endocrine system medicine.medical_specialty Sympathetic nervous system Lactacystin Neuropeptide Apoptosis Chick Embryo Biology Biochemistry Adenylyl cyclase Cellular and Molecular Neuroscience chemistry.chemical_compound Multienzyme Complexes Internal medicine medicine Animals Nerve Growth Factors Cells Cultured Neurons Neurotransmitter Agents Ganglia Sympathetic Forskolin Muscarine Caspase 3 Neuropeptides Cysteine Endopeptidases Pituitary adenylate cyclase-activating peptide Neuroprotective Agents Nerve growth factor Endocrinology medicine.anatomical_structure nervous system chemistry Caspases Pituitary Adenylate Cyclase-Activating Polypeptide hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Journal of Neurochemistry. 71:1889-1897 |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1046/j.1471-4159.1998.71051889.x |
| Popis: | Removal of nerve growth factor (NGF) from sympathetic neurons initiates a neuronal death program and apoptosis. We show that pituitary adenylyl cyclase-activating polypeptide (PACAP) prevents apoptosis in NGF-deprived sympathetic neurons. PACAP (100 nM) added to culture medium at the time of plating failed to support neuronal survival. However, in neurons grown for 2 days with NGF and then deprived of NGF, PACAP prevented cell death for the next 24–48 h. Uptake of [3H]norepinephrine ([3H]NE) was used as an index of survival and decreased >50% in NGF-deprived cultures within 24 h. PACAP (1–100 nM) restored [3H]NE uptake to 92 ± 8% of that of NGF-supported controls. Depolarization-induced [3H]NE release in neurons rescued by PACAP was the same as that in NGF-supported neurons. PACAP rescue was not mimicked by forskolin or 8-bromo-cyclic AMP and was not blocked by the protein kinase A inhibitor Rp-adenosine 3′,5′-cyclic monophosphothioate. Mobilization of phosphatidylinositol by muscarine failed to support NGF-deprived neurons. Thus, PACAP may use novel signaling to promote survival of sympathetic neurons. The apoptosis-associated caspase CPP32 activity increased approximately fourfold during 6 h of NGF withdrawal (145 ± 40 versus 38 ± 17 nmol of substrate cleaved/min/mg of protein) and returned to even below the control level in NGF-deprived, PACAP-rescued cultures (14 ± 7 nmol/min/mg of protein). Readdition of NGF or PACAP to NGF-deprived cultures reversed CPP32 activation, and this was blocked by lactacystin, a potent and specific inhibitor of the 20S proteasome, suggesting that NGF and PACAP target CPP32 for destruction by the proteasome. As PACAP is a preganglionic neurotransmitter in autonomic ganglia, we propose a novel function for this transmitter as an apoptotic rescuer of sympathetic neurons when the supply of NGF is compromised. |
| Databáze: | OpenAIRE |
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