{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ENTPD3 (also known as NTPDase3 or CD39L3) is a plasma membrane–bound ectonucleotidase that hydrolyzes extracellular ATP and ADP to AMP, thereby regulating local purinergic signaling in a wide variety of tissues and physiological contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In pancreatic islets, ENTPD3 is the dominant ectonucleotidase expressed by insulin‐secreting β‐cells; its activity modulates extracellular nucleotide levels and, consequently, glucose‐dependent insulin secretion. Moreover, ENTPD3 expression marks the most mature population of stem cell–derived β‐like cells, suggesting a role in β‐cell maturation and the potential utility of ENTPD3 as a sorting marker for functionally mature cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In the digestive system and airways, ENTPD3 is localized to specific epithelial cells where, in association with other ectonucleotidases, it contributes to the fine‐tuning of extracellular ATP concentrations that drive enteric neurotransmission and inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In the nervous system, ENTPD3 is present in sensory and nociceptive neurons; its catalytic activity regulates extracellular ATP levels in trigeminal pathways, thereby influencing pain signal transduction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Additionally, in vertebrate models, ENTPD3 is expressed in hypocretin (orexin) neurons, implicating this enzyme in sleep regulation and in the processing of sensory inputs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In the tumor microenvironment, the tumor suppressor GATA3 upregulates ENTPD3, which leads to decreased extracellular ATP concentrations, suppression of epithelial–mesenchymal transition, and ultimately reduced metastasis in breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In addition, deletion studies in mice have revealed that loss of ENTPD3 expression confers resistance to diet‐induced obesity and improves glucose tolerance, highlighting a putative role in metabolic regulation that may be independent of its actions in pancreatic β‐cells but related to adipocyte function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, an alternatively spliced variant of ENTPD3 (termed “NTPDase3β”) has been identified, which lacks the C‐terminal transmembrane domain and a conserved catalytic region; this splice variant interferes with the normal processing and surface trafficking of the full‐length enzyme and may therefore serve as an intrinsic mechanism for modulating purinergic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mercedes N Munkonda, Julie Pelletier, Vasily V Ivanenkov, et al. 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