The Expression Level of Ecto-NTP Diphosphohydrolase1/CD39 Modulates Exocytotic and Ischemic Release of Neurotransmitters in a Cellular Model of Sympathetic Neurons

Abstract

Once released, norepinephrine is removed from cardiac synapses via reuptake into sympathetic nerves, whereas transmitter ATP is catabolized by ecto-NTP diphosphohydrolase 1 (ENTPDase1)/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.

Cardiac purinergic signalling in health and disease

“…Conversely, over-expression of E-NTPDase 1/CD39 resulted in enhanced removal of exogenous ATP [618] and protection against murine myocardial ischaemic injury [619]. Since ATP availability greatly increases in myocardial ischaemia, it has been suggested that recombinant E-NTPDase 1/CD39 may offer a novel therapeutic approach to the damage caused by ischaemia by reducing sympathetic activity [618]. E-NTPDase 1/CD39 deletion led to an attenuation of the activity of sympathetic pre-and post-synaptic P2XR (attributed to P2XR desensitisation) perhaps due to prolonged exposure to ATP that accompanies E-NTPDase 1/CD39 deletion, and it was suggested that E-NTPDase 1/CD39 can potentially prevent the transition from myocardial ischaemia to infarction [620].…”

“…Ecto-nucleotidase on sympathetic nerve endings attenuates ATP and NA exocytosis in myocardial ischaemia by reducing ATP levels and consequently the prejunctional facilitatory effects of ATP [580]. Conversely, over-expression of E-NTPDase 1/CD39 resulted in enhanced removal of exogenous ATP [618] and protection against murine myocardial ischaemic injury [619]. Since ATP availability greatly increases in myocardial ischaemia, it has been suggested that recombinant E-NTPDase 1/CD39 may offer a novel therapeutic approach to the damage caused by ischaemia by reducing sympathetic activity [618].…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…Ectonucleotidase on sympathetic nerve endings attenuates ATP and NA exocytosis in myocardial ischemia (by reducing ATP levels and consequently the prejunctional facilitatory effects of ATP) (Sesti et al, 2003). Conversely, overexpression of E-NTPDase 1/CD39 resulted in enhanced removal of exogenous ATP (Corti et al, 2011) and protection against murine myocardial ischemic injury (Cai et al, 2011). Because ATP availability greatly increases in myocardial ischemia, it has been suggested that recombinant E-NTPDase 1/CD39 may offer a novel therapeutic approach to the damage caused by ischemia by reducing sympathetic activity (Corti et al, 2011).…”

“…Conversely, overexpression of E-NTPDase 1/CD39 resulted in enhanced removal of exogenous ATP (Corti et al, 2011) and protection against murine myocardial ischemic injury (Cai et al, 2011). Because ATP availability greatly increases in myocardial ischemia, it has been suggested that recombinant E-NTPDase 1/CD39 may offer a novel therapeutic approach to the damage caused by ischemia by reducing sympathetic activity (Corti et al, 2011). E-NTPDase 1/CD39 deletion led to an attenuation of the activity of sympathetic pre-and postsynaptic P2X receptors (attributed to P2X receptor desensitization) perhaps because of prolonged exposure to ATP that accompanies E-NTPDase 1/CD39 deletion, and it was suggested that E-NTPDase 1/CD39 can potentially prevent the transition from myocardial ischemia to infarction (Schaefer et al, 2007).…”

Aldehyde Dehydrogenase Type 2 Activation by Adenosine and Histamine Inhibits Ischemic Norepinephrine Release in Cardiac Sympathetic Neurons: Mediation by Protein Kinase Cε

“…at ASPET Journals on May 9, 2018 jpet.aspetjournals.org ron (Morrey et al, 2008;Corti et al, 2011). We found that Alda-1 (100 M; 20 min) elicited a Ն60% increase in ALDH2 activity (Fig.…”