These multiple forms (isoforms or subtypes) of phosphodiesterase were isolated from rat brain using polyacrylamide gel electrophoresis in the early 1970s by Weiss and coworkers, and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues.
The PDE nomenclature signifies the PDE family with an Arabic numeral, then a capital letter denotes the gene in that family, and a second and final Arabic numeral then indicates the splice variant derived from a single gene (e.g., PDE1C3: family 1, gene C, splicing variant 3).
The superfamily of PDE enzymes is classified into 11 families, namely PDE1-PDE11, in mammals. The classification is based on:
PDE substrate specificities by enzyme family. Both means it hydrolyzes both cAMP and cGMP.
Different PDEs of the same family are functionally related despite the fact that their amino acid sequences can show considerable divergence. PDEs have different substrate specificities. Some are cAMP-selective hydrolases (PDE4, 7 and 8); others are cGMP-selective (PDE5, 6, and 9). Others can hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10, and 11). PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase. Although PDE2 can hydrolyze both cyclic nucleotides, binding of cGMP to the regulatory GAF-B domain will increase cAMP affinity and hydrolysis to the detriment of cGMP. This mechanism, as well as others, allows for cross-regulation of the cAMP and cGMP pathways. PDE12 cleaves 2',5'-phosphodiester bond linking adenosines of the 5'-triphosphorylated oligoadenylates. PDE12 is not a member of the cyclic nucleotide phosphodiesterase superfamily that contains PDE1 through PDE11.
Phosphodiesterase enzymes have been shown to be different in different types of cells, including normal and leukemic lymphocytes and are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties.
Inhibitors of PDE can prolong or enhance the effects of physiological processes mediated by cAMP or cGMP by inhibition of their degradation by PDE.
Paraxanthine, the main metabolite of caffeine, is another cGMP-specific phosphodiesterase inhibitor which inhibits PDE9, a cGMP preferring phosphodiesterase. PDE9 is expressed as high as PDE5 in the corpus cavernosum.
PDE also are important in seizure incidence. For example, PDE compromised the antiepileptic activity of adenosine. In addition, using of a PDE inhibitor (pentoxifylline) in pentylenetetrazole-induced seizure indicated the antiepileptic effect by increasing the time latency to seizure incidence and decreasing the seizure duration in vivo.
Sildenafil, Tadalafil and Vardenafil are PDE-5 inhibitors and are widely used in the treatment of erectile dysfunction.
^Uzunov P, Weiss B (September 1972). "Separation of multiple molecular forms of cyclic adenosine-3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis". Biochimica et Biophysica Acta. 284 (1): 220–6. doi:10.1016/0005-2744(72)90060-5. PMID4342220.
^Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T (June 2005). "Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system". Biochemistry. 44 (23): 8312–25. doi:10.1021/bi047313h. PMID15938621.
^Jeon YH, Heo YS, Kim CM, Hyun YL, Lee TG, Ro S, Cho JM (June 2005). "Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development". Cellular and Molecular Life Sciences. 62 (11): 1198–220. doi:10.1007/s00018-005-4533-5. PMID15798894. S2CID9806864.
^Rang, HP; Ritter, JM; Flower, RJ; Henderson, G (2016). Rang & Dale's Pharmacology (8th ed.). Churchill Livingstone. p. 349. ISBN978-0-7020-5362-7.
^Hosseini-Zare MS, Salehi F, Seyedi SY, Azami K, Ghadiri T, Mobasseri M, Gholizadeh S, Beyer C, Sharifzadeh M (November 2011). "Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice". European Journal of Pharmacology. 670 (2–3): 464–70. doi:10.1016/j.ejphar.2011.09.026. PMID21946102.