The phosphodiesterase 4 (PDE4) subfamily
| PDE4 subtype | Organ systems | Variant localisation# | Knockout phenotype | References |
| A (A1–11) | Ubiquitous, with variant-specific tissue distribution; high levels in adipose tissue, brain, heart and testes | • PDE4A4B: T-cells, monocytes, neutrophils • PDE4A7: bronchoalveolar macrophages, peripheral blood monocytes, T-cells, neutrophils • PDE4A10: bronchoalveolar macrophages, peripheral blood monocytes, T-cells, neutrophils, heart and small intestine; present in adult brain but not fetal brain • PDE4A11: various tissues, with high expression in fetal, but not adult, brain | • Increased anxiogenic-like behaviour • Increased emotional memory | [20, 22, 113–115] |
| B (B1–5) | Widely distributed, with variant-specific tissue distribution; high levels in brain, lung, immune cells, heart and skeletal muscle | • PDE4B1: bronchoalveolar macrophages, peripheral blood monocytes, T-cells • PDE4B2: bronchoalveolar macrophages, peripheral blood monocytes, T-cells, leukocytes, especially neutrophils; major PDE4B subtype in normal B-cells, abundant in naïve and memory B-cells, low in centroblasts and centrocytes | • No airway inflammation or acute airway hyperactivity in response to allergen challenge • Inhibited TGF-β-induced differentiation into myofibroblasts • Inhibited injury-induced neutrophil recruitment • Reduced inflammatory response to LPA in monocytes and macrophages • Inhibition of TNF-α production • Decreased striatal dopamine and 5-HT activity, associated with reduced pre-pulse inhibition and baseline motor activity • Increased anxiogenic-like behaviour | [22, 29, 116–123] |
| C (1–5) | Testes and other tissues; low in lung, absent in blood and immune cells | • PDE4C-Δ54: testes-specific • PDE4C1–3: identified in human tissue, although there are limited data on expression of PDE4C variants | • None published | [20, 21, 124] |
| D (D1–9) | Brain, skeletal muscle and immune cells | • PDE4D1: bronchoalveolar macrophages, peripheral blood monocytes, T-cells, neutrophils • PDE4D2: bronchoalveolar macrophages, peripheral blood monocytes, T-cells • PDE4D3: bronchoalveolar macrophages, peripheral blood monocytes, T-cells • PDE4D4: brain-specific • PDE4D6: brain-specific • PDE4D7: ubiquitous, with high levels in lung and kidney • PDE4D8: heart and skeletal muscle, indicating muscle-specific expression • PDE4D5: dominant in well-differentiated human bronchial epithelium cells | • Inhibited injury-induced neutrophil recruitment • Impaired airway contractile responses induced by cholinergic stimulation, and little or no airway hyper-reactivity induced by exposure to allergen • Delayed growth, impaired ovulation, reduced postnatal viability and refractory to muscarinic cholinergic stimulation • Loss of β2-, but not β1-, adrenergic receptor-regulated responses in cardiac cells • Growth inhibition and apoptotic cell death in malignant cells, but not in nonmalignant cells • Anti-depressive behaviour and reduced antidepressant responses to rolipram • Enhanced performance in memory tasks, and increased hippocampal neurogenesis and phosphorylated CREB • Increased emesis | [33, 40, 117, 125–130] |
#: variant localisation based on data from human tissue samples and human PDE4-subtype gene expression in vitro. 5-HT: 5-hydroxytryptamine; CREB: cyclic adenosine monophosphate response element-binding protein; LPA: lysophosphatidic acid; PDE: phosphodiesterase; TGF-β: transforming growth factor-β; TNF-α: tumour necrosis factor-α.