{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPhosphodiesterase‐4A (PDE4A) isoforms are critical regulators of intracellular cyclic AMP (cAMP) signaling through their ability to catalyze cAMP degradation in a spatially and temporally controlled manner. Different splice variants—including long forms such as PDE4A1, PDE4A4, PDE4A5, PDE4A8, PDE4A10, and PDE4A11—exhibit unique N‐terminal domains that dictate subcellular targeting, membrane association, and interaction with discrete signaling complexes. For example, a short helical motif in PDE4A1 governs its selective membrane binding via a phosphatidic acid–selective module, while alternative N‐terminal sequences in PDE4A10 and PDE4A11 confer distinct catalytic properties, subcellular localization, and sensitivities to protein kinase A activation and inhibitors. These studies underscore that isoform diversity within PDE4A is central to shaping compartmentalized cAMP dynamics in diverse tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its intrinsic catalytic role, PDE4A interacts with several regulatory and scaffolding proteins that modulate its activity and thereby impact diverse cell functions. Specific interactions—with proteins such as the immunophilin XAP2 (via PDE4A5), the risk factor DISC1 in the cerebellum, and the p75 neurotrophin receptor in tissue remodeling—demonstrate that PDE4A not only governs local cAMP concentrations but also influences cellular processes including T‐cell activation, epithelial‐mesenchymal transition in lung epithelial cells, and excitation–contraction coupling in cardiomyocytes. Moreover, PDE4A expression is dynamically regulated in response to stimuli in inflammatory and vascular cells, and its modulation by selective inhibitors (for example, rolipram and GSK256066) further reveals a key role in controlling receptor‐mediated responses, cell proliferation, angiogenesis, and even immune cell adhesion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, dysregulation of PDE4A function is implicated in a range of pathological conditions. Aberrant expression and altered protein–protein interactions of PDE4A isoforms have been linked to oncogenesis in brain tumors and pituitary adenomas, contribute to immune cell function in chronic lymphocytic leukemia and sepsis, and modulate neuronal survival in experimental models of Parkinson’s disease. In addition, PDE4A disturbances influence autophagy‐dependent epithelial–mesenchymal transition in hepatocarcinoma cells and support the control of atrial cAMP signals in arrhythmia. The therapeutic targeting of PDE4A—by agents such as roflumilast, apremilast, and novel compounds like FCPR16—thus holds promise for treating a diverse set of diseases including inflammatory disorders, neurodegenerative conditions, and cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "G Rena, F Begg, A Ross, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "TAPAS-1, a novel microdomain within the unique N-terminal region of the PDE4A1 cAMP-specific phosphodiesterase that allows rapid, Ca2+-triggered membrane association with selectivity for interaction with phosphatidic acid."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M108353200"}], "href": "https://doi.org/10.1074/jbc.M108353200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11994273"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11994273"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Graeme B Bolger, Alexander H Peden, Michael R Steele, et al. 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