The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance Simon C. Robson, Jean Sévigny, Herbert Zimmermann Abstract: Ectonucleotidases are ectoenzymes that hydrolyze extracellular nucleotides to nucleosides. In the past decade, several ectonucleotidase families have been discovered, cloned, and characterized. This article focuses on the cell surface-located members of the E-NTPDase/CD39 family (NTPDase1, 2, 3, and 8). Molecular identification, genetic engineering, mutational analyses, and the generation of subtype-specific antibodies have provided significant insights into enzyme structure and function. These advances have also defined the physiological and pathophysiological implications of NTPDases in various tissues. Biological actions of NTPDases are a consequence of regulated phosphohydrolytic activity on extracellular nucleotides and subsequent effects on P2-receptor signaling. The spatial and temporal expression of NTPDases by various cell types in the vasculature, nervous tissues, and other tissues impacts several pathophysiological processes. Examples include acute effects on cellular metabolism, adhesion, activation, and migration, as well as protracted impacts on developmental responses, including cellular proliferation, differentiation, and apoptosis, seen in atherosclerosis, degenerative neurological diseases, and immune rejection of transplanted organs and cells. Future clinical applications are expected to involve the development of new therapeutic strategies for transplantation and various inflammatory cardiovascular, gastrointestinal, and neurological diseases. Keywords: apyrase, brain, CD39, ecto-ATPase, immunology, ischemia, kidney, liver, nervous tissue, NTPDase, platelet, vasculature Abstract: Extracellular nucleotides modulate a variety of tissue functions, including development, blood flow, secretion, inflammation, and immune reactions. Signaling via extracellular nucleotides has been recognized as one of the most ubiquitous intercellular signaling mechanisms. Essentially every cell in a mammalian organism leaks or releases these mediators, and carries receptors for nucleotides of which seven ionotropic (P2X) and at least eight metabotropic (P2Y) receptor subtypes have been identified and characterized. Whereas P2X receptors respond to ATP, P2Y receptors can be activated by ATP, ADP, UTP, UDP, ITP, and nucleotide sugars, albeit agonist specificity varies between subtypes and the multiple animal species. Depending on the P2 receptor subtype and signaling pathways involved, these receptors trigger and mediate short-term (acute) processes that affect cellular metabolism, adhesion, activation, or migration. In addition, purinergic signaling also has profound impacts upon other more protracted responses, including cell proliferation, differentiation, and apoptosis, such as seen in atherosclerosis,The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance Simon C. Robson, Jean Sévigny, Herbert Zimmermann Abstract: Ectonucleotidases are ectoenzymes that hydrolyze extracellular nucleotides to nucleosides. In the past decade, several ectonucleotidase families have been discovered, cloned, and characterized. This article focuses on the cell surface-located members of the E-NTPDase/CD39 family (NTPDase1, 2, 3, and 8). Molecular identification, genetic engineering, mutational analyses, and the generation of subtype-specific antibodies have provided significant insights into enzyme structure and function. These advances have also defined the physiological and pathophysiological implications of NTPDases in various tissues. Biological actions of NTPDases are a consequence of regulated phosphohydrolytic activity on extracellular nucleotides and subsequent effects on P2-receptor signaling. The spatial and temporal expression of NTPDases by various cell types in the vasculature, nervous tissues, and other tissues impacts several pathophysiological processes. Examples include acute effects on cellular metabolism, adhesion, activation, and migration, as well as protracted impacts on developmental responses, including cellular proliferation, differentiation, and apoptosis, seen in atherosclerosis, degenerative neurological diseases, and immune rejection of transplanted organs and cells. Future clinical applications are expected to involve the development of new therapeutic strategies for transplantation and various inflammatory cardiovascular, gastrointestinal, and neurological diseases. Keywords: apyrase, brain, CD39, ecto-ATPase, immunology, ischemia, kidney, liver, nervous tissue, NTPDase, platelet, vasculature Abstract: Extracellular nucleotides modulate a variety of tissue functions, including development, blood flow, secretion, inflammation, and immune reactions. Signaling via extracellular nucleotides has been recognized as one of the most ubiquitous intercellular signaling mechanisms. Essentially every cell in a mammalian organism leaks or releases these mediators, and carries receptors for nucleotides of which seven ionotropic (P2X) and at least eight metabotropic (P2Y) receptor subtypes have been identified and characterized. Whereas P2X receptors respond to ATP, P2Y receptors can be activated by ATP, ADP, UTP, UDP, ITP, and nucleotide sugars, albeit agonist specificity varies between subtypes and the multiple animal species. Depending on the P2 receptor subtype and signaling pathways involved, these receptors trigger and mediate short-term (acute) processes that affect cellular metabolism, adhesion, activation, or migration. In addition, purinergic signaling also has profound impacts upon other more protracted responses, including cell proliferation, differentiation, and apoptosis, such as seen in atherosclerosis,