Ectonucleoside triphosphate diphosphohydrolase 1/CD39, localized in neurons of human and porcine heart, modulates ATP-induced norepinephrine exocytosis. Academic Article uri icon

Overview

abstract

  • Using a guinea pig heart synaptosomal preparation, we previously observed that norepinephrine (NE) exocytosis was attenuated by a blockade of P2X purinoceptors, potentiated by inhibition of ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1)/CD39, and reduced by soluble CD39, a recombinant form of human E-NTPDase1/CD39. This suggests that norepinephrine and ATP are coreleased upon depolarization of cardiac sympathetic nerve endings and that ATP enhances norepinephrine exocytosis by an action modulated by E-NTPDase1/CD39 activity. Whether E-NTPDase1/CD39 is localized to cardiac neurons and modulates norepinephrine exocytosis in intact heart tissue remained untested. We report that E-NTPDase1/CD39 is selectively localized in human and porcine cardiac neurons and that depolarization of porcine heart tissue elicits omega-conotoxin-inhibitable release of both norepinephrine and ATP. Inhibition of E-NTPDase1/CD39 with ARL67156 markedly potentiated ATP release, demonstrating that E-NTPDase1/CD39 is a major determinant of ATP availability at sympathetic nerve terminals. Notably, inhibition of E-NTPDase1/CD39 enhanced both ATP and NE exocytosis, whereas administration of soluble CD39 reduced both ATP and NE exocytosis. The strong correlation between ATP and norepinephrine release was abolished in the presence of the purinergic P2X receptor (P2XR) antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). We conclude that released ATP governs norepinephrine exocytosis by activating presynaptic P2XR and that this action is controlled by neuronal E-NTPDase1/CD39. Clinically, excessive norepinephrine release is a major cause of arrhythmic and coronary vascular dysfunction during myocardial ischemia. By curtailing NE release, in addition to its effects as an antithrombotic agent, soluble CD39 may constitute a novel therapeutic approach to ischemic complications in the myocardium.

publication date

  • January 12, 2005

Research

keywords

  • Adenosine Triphosphatases
  • Adenosine Triphosphate
  • Antigens, CD
  • Apyrase
  • Exocytosis
  • Myocardium
  • Neurons
  • Norepinephrine
  • Pyridoxal Phosphate

Identity

Scopus Document Identifier

  • 18044396559

Digital Object Identifier (DOI)

  • 10.1124/jpet.104.081240

PubMed ID

  • 15647328

Additional Document Info

volume

  • 313

issue

  • 2