Targeted deletion of ectonucleoside triphosphate diphosphohydrolase 1/CD39 leads to desensitization of pre- and postsynaptic purinergic P2 receptors
Receptors, Purinergic P2
We previously reported that ATP coreleased with norepinephrine from cardiac sympathetic nerves activates presynaptic P2X purinoceptors (P2XR), thereby enhancing norepinephrine exocytosis. Blockade of ectonucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1/CD39) potentiates norepinephrine exocytosis, whereas recombinant soluble CD39 (solCD39) in-hibits it. This suggested that CD39 gene (Entpd1) deletion would enhance purinergic and adrenergic signaling by preserving ATP and its norepinephrine-releasing activity. However, we found that the neurogenic contractile response of vasa deferentia from Entpd1-null (CD39(-/-)) mice was attenuated and accompanied by reduced activity of pre- and postsynaptic P2XR, whereas contractile responses to K(+) or norepinephrine remained intact. In addition, the magnitude of ATP and norepinephrine exocytosis from cardiac synaptosomes was decreased in CD39(-/-) mice. Inhibition of E-NTPDase1/CD39, or solCD39 administration, did not affect the attenuated contractile response of vasa deferentia from CD39(-/-) mice. Notably, Entpd1 deletion and pharmacological P2XR desensitization in control mice similarly attenuated vasa deferentia responses. Thus, excessive and prolonged ATP exposure resulting from CD39 deletion desensitizes pre- and postjunctional P2XR at the sympathetic neuromuscular junction. This diminishes purinergic activity directly and adrenergic activity indirectly. It remains to be determined whether this desensitization results from receptor internalization, changes in receptor conformation or phosphorylation. Shutdown of ATP signaling in CD39(-/-) mice may represent a defense mechanism for the prevention of purinergic overstimulation. Our findings emphasize the cardioprotective role of neuronal CD39: by reducing presynaptic facilitatory effects of neurotransmitter ATP, CD39 attenuates norepinephrine release and its dysfunctional consequences. Moreover, by virtue of its antithrombotic action CD39 can potentially prevent the transition from myocardial ischemia to infarction.