3',5'-Cyclic nucleotide phosphodiesterases (PDEs, 3',5'-cyclic-nucleotide 5'-nucleotidohydrolase), E.C. 3.1.4.17, catalyse the hydrolysis of a 3',5'-cyclic nucleotide (usually cyclic AMP or cyclic GMP). Isobutylmethylxanthine is a nonselective inhibitor with an IC₅₀ value in the millimolar range for all isoforms except PDE 8A, 8B and 9A. A 2',3'-cyclic nucleotide 3'-phosphodiesterase (E.C. 3.1.4.37 CNPase) activity is associated with myelin formation in the development of the CNS.

PDE1A, 1B and 1C appear to act as soluble homodimers, while PDE2A is a membrane-bound homodimer. PDE3A and PDE3B are membrane-bound.

PDE4 isoforms are essentially cyclic AMP specific. The potency of YM976 at other members of the PDE4 family has not been reported. PDE4B–D long forms are inhibited by extracellular signal-regulated kinase (ERK)-mediated phosphorylation [16-17]. PDE4A–D splice variants can be membrane-bound or cytosolic [18]. PDE4 isoforms may be labelled with [³H]rolipram.

PDE6 is a membrane-bound tetramer composed of two catalytic chains (PDE6A or PDE6C and PDE6B), an inhibitory chain (PDE6G or PDE6H) and the PDE6D chain. The enzyme is essentially cyclic GMP specific and is activated by the α-subunit of transducin (Gα_t) and inhibited by sildenafil, zaprinast and dipyridamole with potencies lower than those observed for PDE5A. Defects in PDE6B are a cause of retinitis pigmentosa and congenital stationary night blindness.

* Key recommended reading is highlighted with an asterisk

* Das A, Durrant D, Salloum FN, Xi L, Kukreja RC. (2015) PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer. Pharmacol. Ther., 147: 12-21. [PMID:25444755]

* Jørgensen C, Yasmeen S, Iversen HK, Kruuse C. (2015) Phosphodiesterase4D (PDE4D)--A risk factor for atrial fibrillation and stroke?. J. Neurol. Sci., 359 (1-2): 266-74. [PMID:26671126]

* Klussmann E. (2016) Protein-protein interactions of PDE4 family members - Functions, interactions and therapeutic value. Cell. Signal., 28 (7): 713-8. [PMID:26498857]

* Korkmaz-Icöz S, Radovits T, Szabó G. (2018) Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure. Br. J. Pharmacol., 175 (2): 223-231. [PMID:28213937]

* Leal LF, Szarek E, Faucz F, Stratakis CA. (2015) Phosphodiesterase 8B and cyclic AMP signaling in the adrenal cortex. Endocrine, 50 (1): 27-31. [PMID:25971952]

* Movsesian M. (2016) Novel approaches to targeting PDE3 in cardiovascular disease. Pharmacol. Ther., 163: 74-81. [PMID:27108947]

* Ricciarelli R, Fedele E. (2015) Phosphodiesterase 4D: an enzyme to remember. Br. J. Pharmacol., 172 (20): 4785-9. [PMID:26211680]

* Wu C, Rajagopalan S. (2016) Phosphodiesterase-4 inhibition as a therapeutic strategy for metabolic disorders. Obes Rev, 17 (5): 429-41. [PMID:26997580]

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Chen Yan, Ph.D. University of Rochester School of Medicine and Dentistry 601 Elmwood Ave, Box CVRI Rochester, NY 14642