{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPhosphodiesterase 4B (PDE4B) is a cAMP‐specific hydrolase that plays a critical role in the regulation of intracellular signaling in the brain. In neuronal cells, PDE4B modulates the cyclic AMP cascade and contributes to the fine‐tuning of diverse signaling pathways. Notably, PDE4B interacts with the DISC1 protein, a well‐established risk factor for major psychiatric disorders, thereby influencing the availability of cAMP and subsequently affecting neuronal plasticity, learning, memory, and mood regulation. Disruption of DISC1–PDE4B complexes has been implicated in schizophrenia, bipolar disorder, depression, Huntington’s disease, and even glioblastoma, with specific brain‐expressed isoforms (such as the super‐short PDE4B5) being central to these processes. Altered binding affinities and dysregulation of PDE4B expression appear to underlie abnormal intracellular signaling linked to neuropsychiatric pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond the nervous system, PDE4B exerts crucial control over inflammatory and immunologic responses in various cell types. In immune cells such as T lymphocytes and monocytes, activation of the T cell receptor or Toll‐like receptors directs a rapid induction of PDE4B isoforms (for instance, PDE4B2) that locally regulate cAMP levels, thereby affecting cytokine production and cell proliferation. In addition, PDE4B influences non‐neuronal processes in lung fibroblasts, cardiac myocytes, and astrocytes by shaping intracellular cAMP gradients, which modulate responses to pro‐inflammatory stimuli. In models of chronic inflammatory conditions—ranging from diffuse large B-cell lymphoma and chronic obstructive pulmonary disease to otitis media and placental inflammation—alterations in PDE4B expression or activity have been shown to impact processes such as apoptosis, chemokine induction, mucin production, and tissue fibrosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPDE4B also plays significant roles in oncogenesis by regulating cell proliferation and survival. A feed-forward loop between Myc and PDE4B has been identified in B cell lymphomas, where increased PDE4B activity sustains proliferative signals via modulation of intracellular cAMP, thereby contributing to an aggressive tumor phenotype. In the colon, preserved PDE4B function in the normal epithelium adjacent to adenomas suggests a protective mechanism against tumorigenesis, whereas loss of PDE4B activity is associated with enhanced adenoma formation. Moreover, recent evidence indicates that genetic variants in PDE4B may affect relapse in acute lymphoblastic leukemia, underscoring the importance of this enzyme as a potential therapeutic target in hematological malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, the catalytic mechanism of PDE4B has been characterized using combined quantum mechanical and molecular mechanical simulations. These studies reveal that PDE4B hydrolyzes cAMP via an S(N)2-type mechanism with a coupled phosphoryl transfer and protonation step that effectively stabilizes the transition state, highlighting the enzyme’s remarkable efficiency in lowering the energetic barrier for cAMP degradation. This mechanistic insight provides a structural basis for the development of targeted PDE4B inhibitors with potential therapeutic utility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J Kirsty Millar, Benjamin S Pickard, Shaun Mackie, et al. 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