The Journal of pharmacology and experimental therapeutics, 2011-05, Vol.337 (2), p.524-532
2011
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- Autor(en) / Beteiligte
- Titel
- The expression level of ecto-NTP diphosphohydrolase1/CD39 modulates exocytotic and ischemic release of neurotransmitters in a cellular model of sympathetic neurons
- Ist Teil von
- The Journal of pharmacology and experimental therapeutics, 2011-05, Vol.337 (2), p.524-532
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Once released, norepinephrine is removed from cardiac synapses via reuptake into sympathetic nerves, whereas transmitter ATP is catabolized by ecto-NTP diphosphohydrolase 1 (E-NTPDase1)/CD39, an ecto-ATPase. Because ATP is known to modulate neurotransmitter release at prejunctional sites, we questioned whether this action may be ultimately controlled by the expression of E-NTPDase1/CD39 at sympathetic nerve terminals. Accordingly, we silenced E-NTPDase1/CD39 expression in nerve growth factor-differentiated PC12 cells, a cellular model of sympathetic neuron, in which dopamine is the predominant catecholamine. We report that E-NTPDase1/CD39 deletion markedly increases depolarization-induced exocytosis of ATP and dopamine and increases ATP-induced dopamine release. Moreover, overexpression of E-NTPDase1/CD39 resulted in enhanced removal of exogenous ATP, a marked decrease in exocytosis of ATP and dopamine, and a large decrease in ATP-induced dopamine release. Administration of a recombinant form of E-NTPDase1/CD39 reproduced the effects of E-NTPDase1/CD39 overexpression. Exposure of PC12 cells to simulated ischemia elicited a release of ATP and dopamine that was markedly increased in E-NTPDase1/CD39-silenced cells and decreased in E-NTPDase1/CD39-overexpressing cells. Therefore, transmitter ATP acts in an autocrine manner to promote its own release and that of dopamine, an action that is controlled by the level of E-NTPDase1/CD39 expression. Because ATP availability greatly increases in myocardial ischemia, recombinant E-NTPDase1/CD39 therapeutically used may offer a novel approach to reduce cardiac dysfunctions caused by excessive catecholamine release.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-3565eISSN: 1521-0103DOI: 10.1124/jpet.111.179994Titel-ID: cdi_pubmed_primary_21325440
- Format
- –
- Schlagworte
- Adenosine Triphosphate - metabolism, Animals, Antigens, CD - biosynthesis, Antigens, CD - genetics, Apyrase - biosynthesis, Apyrase - genetics, Blotting, Western, DNA Primers, Dopamine - metabolism, Exocytosis - genetics, Exocytosis - physiology, Gene Expression Regulation, Enzymologic - physiology, Gene Silencing, Ischemia - metabolism, Nerve Growth Factors - pharmacology, Neurons - metabolism, Neurotransmitter Agents - metabolism, Norepinephrine - metabolism, PC12 Cells, Potassium - pharmacology, Rats, Receptors, Purinergic P2X - drug effects, Receptors, Purinergic P2X - metabolism, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering - metabolism, Sympathetic Nervous System - cytology, Sympathetic Nervous System - metabolism