{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPhosphodiesterase 3B (PDE3B) is a pivotal regulator of intracellular cyclic AMP, integrating structural, metabolic, and signaling roles across a variety of tissues. Genetic screening in Japanese subjects revealed that common PDE3B polymorphisms are unlikely to majorly contribute to type 2 diabetes susceptibility ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]. High‐resolution structural studies of its catalytic domain have uncovered PDE3B’s dual cyclic nucleotide (cAMP/cGMP) binding properties and provided the molecular basis for selective inhibitor design ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "]. In the heart, PDE3B is recruited into a noncatalytic scaffolding complex via direct interaction with a regulatory subunit (p87[PIKAP]), a feature that appears to be crucial for PI3Kγ‐mediated cardiac signaling ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "]. In pancreatic islets, the enzyme is activated upon high glucose, insulin, and cAMP elevations and undergoes distinct phosphorylation changes that modulate β‑cell function, while its stabilization by ABHD15 in adipocytes is essential for insulin’s anti‐lipolytic actions ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn other cellular contexts, PDE3B functions as a local “gatekeeper” of cAMP signals. For example, in HEK293T cells PDE3B selectively integrates into EPAC1‐based complexes to help govern cell adhesion dynamics ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "]. In erythrocytes, PDE3B is present in the membrane where its activity modulates iloprost‐induced cAMP elevations and the downstream release of ATP—an important mechanism for regulating microvascular perfusion ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "]. Moreover, in head and neck squamous cell carcinoma, elevated PDE3B expression has been associated with chemoresistance to cisplatin, with gene silencing increasing apoptosis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "]. In arterial endothelial cells, direct binding of PDE3B to both EPAC1 and the PI3Kγ regulatory protein p84 defines a “signalosome” that regulates localized cAMP pools and, thereby, controls cell adhesion, spreading, and tubule formation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]. Furthermore, in adipose tissue from obese subjects, increased S‑nitrosylation of PDE3B correlates with impaired insulin-mediated anti‐lipolysis, while in type 2 diabetic erythrocytes, restoration of PDE3B-mediated signaling by inhibitors such as cilostazol rescues ATP release ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "]. Finally, PDE3B’s role in overall energy homeostasis extends to the regulation of lipolysis, glycogenolysis, gluconeogenesis, and β‑cell insulin secretion ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its metabolic and vascular functions, emerging studies implicate PDE3B in hormonal signaling and tumor biology. In atrial myocytes, reduced PDE3B-associated cAMP responses have been linked to attenuated inotropic effects in atrial fibrillation, with combined PDE3 and PDE4 inhibition able to restore these responses ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "]. Rare germline variants in PDE3B have been detected in patients with primary aldosteronism caused by bilateral adrenal hyperplasia, suggesting that alterations in its expression can affect aldosterone regulation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "]. In the tumor setting, decreased PDE3B expression in bladder cancer is associated with reduced invasion and migration—likely via modulation of keratin 6B expression—while a circular RNA derived from PDE3B (circPDE3B) has been implicated in facilitating esophageal squamous cell carcinoma progression, potentially through mechanisms linked to ferroptosis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "].\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "R Sano, T Miki, Y Suzuki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Analysis of the insulin-sensitive phosphodiesterase 3B gene in type 2 diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes Res Clin Pract (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0168-8227(01)00287-x"}], "href": "https://doi.org/10.1016/s0168-8227(01"}, {"type": "t", "text": "00287-x) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11640991"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11640991"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Giovanna Scapin, Sangita B Patel, Christine Chung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi049868i"}], "href": "https://doi.org/10.1021/bi049868i"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15147193"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15147193"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Philipp Voigt, Martin B Dorner, Michael Schaefer "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase gamma that is highly expressed in heart and interacts with PDE3B."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M512502200"}], "href": "https://doi.org/10.1074/jbc.M512502200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16476736"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16476736"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Daniel Palmer, Sandra L Jimmo, Daniel R Raymond, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protein kinase A phosphorylation of human phosphodiesterase 3B promotes 14-3-3 protein binding and inhibits phosphatase-catalyzed inactivation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M606936200"}], "href": "https://doi.org/10.1074/jbc.M606936200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17255105"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17255105"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wenmin Xia, Ariane R Pessentheiner, Dina C Hofer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2018.04.055"}], "href": "https://doi.org/10.1016/j.celrep.2018.04.055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29768196"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29768196"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Daniel R Raymond, Lindsay S Wilson, Rhonda L Carter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Numerous distinct PKA-, or EPAC-based, signalling complexes allow selective phosphodiesterase 3 and phosphodiesterase 4 coordination of cell adhesion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2007.08.005"}], "href": "https://doi.org/10.1016/j.cellsig.2007.08.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17884339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17884339"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Madelyn S Hanson, Alan H Stephenson, Elizabeth A Bowles, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphodiesterase 3 is present in rabbit and human erythrocytes and its inhibition potentiates iloprost-induced increases in cAMP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Heart Circ Physiol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpheart.00349.2008"}], "href": "https://doi.org/10.1152/ajpheart.00349.2008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18586889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18586889"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yukio Yamano, Katsuhiro Uzawa, Kengo Saito, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of cisplatin-resistance related genes in head and neck squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.24704"}], "href": "https://doi.org/10.1002/ijc.24704"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19569180"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19569180"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Lindsay S Wilson, George S Baillie, Lisa M Pritchard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A phosphodiesterase 3B-based signaling complex integrates exchange protein activated by cAMP 1 and phosphatidylinositol 3-kinase signals in human arterial endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.217026"}], "href": "https://doi.org/10.1074/jbc.M110.217026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21393242"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21393242"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Hilla Ovadia, Yulia Haim, Ori Nov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased adipocyte S-nitrosylation targets anti-lipolytic action of insulin: relevance to adipose tissue dysfunction in obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.235945"}], "href": "https://doi.org/10.1074/jbc.M111.235945"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21724851"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21724851"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Randy S Sprague, Elizabeth A Bowles, David Achilleus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A selective phosphodiesterase 3 inhibitor rescues low PO2-induced ATP release from erythrocytes of humans with type 2 diabetes: implication for vascular control."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Heart Circ Physiol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpheart.00729.2011"}], "href": "https://doi.org/10.1152/ajpheart.00729.2011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21963837"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21963837"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Eva Degerman, Faiyaz Ahmad, Youn Wook Chung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "From PDE3B to the regulation of energy homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Opin Pharmacol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.coph.2011.09.015"}], "href": "https://doi.org/10.1016/j.coph.2011.09.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22001403"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22001403"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Bernardo Dolce, Torsten Christ, Nefeli Grammatika Pavlidou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Naunyn Schmiedebergs Arch Pharmacol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00210-020-01968-1"}], "href": "https://doi.org/10.1007/s00210-020-01968-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32949251"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32949251"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Marcela Rassi-Cruz, Andrea G Maria, Fabio R Faucz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocr Relat Cancer (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/ERC-20-0384"}], "href": "https://doi.org/10.1530/ERC-20-0384"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33112806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33112806"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Pengli Zhou, Zhengyang Wu, Qinghui Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel link between circPDE3B and ferroptosis in esophageal squamous cell carcinoma progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ygeno.2023.110761"}], "href": "https://doi.org/10.1016/j.ygeno.2023.110761"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38092323"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38092323"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Yuankang Feng, Zhenlin Huang, Liang Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PDE3B regulates KRT6B and increases the sensitivity of bladder cancer cells to copper ionophores."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Naunyn Schmiedebergs Arch Pharmacol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00210-023-02928-1"}], "href": "https://doi.org/10.1007/s00210-023-02928-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38165426"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38165426"}]}]}]}