Phosphodiesterase 11: a brief review of structure, expression and function

International Journal of Impotence Research (2006) 18, 501–509 & 2006 Nature Publishing Group All rights reserved 0955-9930/06 $30.00 www.nature.com/ijir REVIEW Phosphodiesterase 11: a brief review of structure, expression and function A Makhlouf, A Kshirsagar and C Niederberger Department of Urology, University of Illinois at Chicago, Chicago, IL, USA Phosphodiesterase 11 (PDE11) is the latest isoform of the phosphodiesterase family to be identified. Interest in PDE11 has increased recently because tadalafil, an oral phosphodiesterase 5 inhibitor, cross reacts with PDE11. The function of PDE11 remains largely unknown, but growing evidence points to a possible role in male reproduction. The published literature on PDE11 structure, function and expression is reviewed. International Journal of Impotence Research (2006) 18, 501–509. doi:10.1038/sj.ijir.3901441; published online 5 January 2006 Keywords: phosphodiesterase; tadalafil; spermatogenesis; erectile dysfunction Introduction Introduction of orally administered phosphodiesterase-5 (PDE5) inhibitors revolutionized the treatment of erectile dysfunction in the past decade.1 Of the 11 known phosphodiesterases (PDEs), PDE5 has been the focus of much attention because it is the protein target of these inhibitors. Sildenafil was the first PDE5 inhibitor to be marketed followed by vardenafil and tadalafil. All three compounds inhibit the catalytic activity of PDE5, thereby preventing the degradation of intracellular cGMP. In turn, cGMP activates cGMP-dependent protein kinase, which phosphorylates a number of intracellular proteins resulting in decreased intracellular calcium concentration and leading to penile smooth muscle relaxation, vasodilatation, and subsequently, penile erection. Recently, there has been an increased interest in PDE11 because tadalafil, one of the newer PDE5 inhibitors approved for treatment of ED, crossreacts with PDE11.2–6 The expression and function of PDE11 are still poorly understood, and this present review will summarize the current state of knowledge regarding PDE11 structure, function and distribution. Emphasis will be placed on the Correspondence: Dr A Makhlouf, Department of Urology, University of Illinois at Chicago, 840 S. Wood Street, MC 955 Chicago, IL 60612-7316, USA. E-mail: Received 2 August 2005; revised 29 November 2005; accepted 29 November 2005; published online 5 January 2006 possible role of PDE11 in spermatogenesis and potential effects, if any, of tadalafil on it. Overview of PDEs Mammalian PDEs are divided into 11 families.1,6 Some families (PDE1, PDE3, PDE4, PDE7 and PDE8) are products of multiple genes (multigene), whereas others derive from a single gene (unigene) (Table 1). Thus, the human genome contains 21 known genes coding for PDEs. Variations in splicing and alternate initiation sites create more variety in each family, with a total number of 53 isoenzymes identified so far.6,7 All PDEs share a highly conserved catalytic domain near the carboxyl-terminus,1 including 11 invariant amino acids in the active site.8 Minor variations in the catalytic domain are believed to be responsible for the different selectivities towards cAMP or cGMP substrate and various inhibitors (Table 1).8 More substantial variation exists in the N-terminus part, where most of the regulatory domains reside.1,9 In the case of PDE11, there is a single gene in the family (PDE11A according to standard nomenclature) with four splicing variants (PDE11A1, PDE11A2, PDE11A3 and PDE11A4). This appears to be the case in all mammalian species studied so far (human, rat and mouse).10–12 Cloning and isolation of PDE11A PDE11A was the latest member of the mammalian PDE family to be identified.13 As the entire human Phosphodiesterase 11 A Makhlouf et al 502 Table 1 Summary of PDE family characteristics1,7–9 PDE family 1 Genes (if multigene) Substrate Inhibitors, Ki or (IC50) Regulation Tissue expression PDE1A PDE1B PDE1C cAMP4cGMP cAMP4cGMP cAMP ¼ cGMP Vinpocetine (14 mM) Zaprinast (6 mM) Sildenafil (0.35 mM) ( þ )Ca2 þ /CAM ()PKA, CamKII 1A: Thyroid, testis, brain 1B: Brain, lymphocytes 1C: Blood vessels, testis cGMPXcAMP EHNA (1 mM) Bay 60-7550 (0.047 mM) ( þ )cGMP, PKC ( þ /)N-terminal-targeting domain Brain, heart, platelets, liver, thymocytes 2 3 PDE3A PDE3B cAMP4cGMP Cilostamide (0.020 mM) Milrinone (0.150 mM) Zardaverine (0.5–2 mM) ( þ )PKA, PKB ()cGMP ( þ /)N-terminal-targeting domain 3A: Heart, blood vessels 3B: Adipocytes, hepatocytes, lymphocytes 4 PDE4A cAMP Rolipram (1 mM) ( þ )PKA, ERK, phosphatidic acid ()ERK, caspases ( þ /)N-terminal-targeting domains 4A: Lung, immune cells, brain, blood vessels Roflumilast (0.8 nM) Cilomilast (120 nM) Zardaverine (0.8–4 mM) PDE4B PDE4C PDE4D 5 cGMP Zaprinast (0.130 mM) Sildenafil (0.10 mM) Vardenafil (0.001 mM) Tadalafil (0.010 mM) ( þ )cGMP, PKG, PKA ()Caspases Smooth muscle, platelets, Purkinje cells, gastrointestinal epithelium, pulmonary endothelium 6 PDE6A PDE6B PDE6C cGMP Zaprinast (0.400 mM) Dipyridamole (0.125 mM) Sildenafil (0.050 mM) Vardenafil (0.011 mM) Tadalafil (2 mM) ( þ )Transducin ()cGMP, gamma and delta subunits Retinal photoreceptors 7 PDE7A PDE7B cAMP IBMX (4 mM) Dipyridamole (0.6 mM) ( þ /)PKA Brain, lymphocytes, kidney 8 PDE8A PDE8B cAMP Dipyridamole (9 mM) PAS domain Thyroid cGMP Zaprinast (35 mM) Unknown Kidney 10 cGMP4cAMP Dipyridamole (1 mM) Zaprinast (22 mM) ()cAMP Testis, brain 11 cAMP and cGMP Zaprinast (12 mM) Dipyridamole (0.4 mM) Unknown Skeletal muscle, prostate, testis, corpus cavernosum, heart (but see text and Table 3) 9 CAM ¼ calmodulin c; ERK ¼ extracellular signal-regulated protein kinase; PAS ¼ periodic acid-Schiff stain; PDE ¼ phosphodiesterase; PKA ¼ protein kinase A; PKC ¼ protein kinase A; PKG ¼ protein kinase G. Only some of the most commonly reported inhibitors for each PDE are listed. Tissue expression is representative of most reports and is not necessarily exhaustive. genome sequence is now available, it appears to be the last. The first published report of PDE11A was by Fawcett et al.,13 who obtained a partial sequence of PDE11A from a commercially available expressed sequence tag (EST) database based on homology with other mammalian PDEs. These investigators then used the PDE11A partial sequence to identify the PDE11A gene from a human skeletal muscle cDNA library. Soon after, the same group cloned PDE11A2 and PDE11A3 cDNAs from a human testis library.12 Almost simultaneously, Yuasa et al.10 International Journal of Impotence Research cloned the A3 and A4 isoforms of PDE11A by PCR with degenerate primers from the conserved catalytic domain of other PDEs, using a human multitissue cDNA library template. No other variants of human PDE11A have since been reported. Gene structure of PDE11A Among the mammalian superfamily of PDEs, PDE11 is phylogenetically related to the other GAF- Phosphodiesterase 11 A Makhlouf et al 5 (...truncated)